Barry I. Rosenblum, DPM, FACFAS

• Assistant Clinical Professor, Surgery
• Harvard Medical School
• Director of Podiatric Surgical Residency
• Beth Israel Deaconess Medical Center
• Boston, Massachusetts

Like Na channels medications ritalin order cheap brahmi on-line, Ca2 channels have a principal subunit symptoms xanax abuse cheap brahmi 60 caps otc, designated 1 treatment resistant anxiety order discount brahmi online, which is structurally homologous to the Na channel subunit medicine 6 year program buy 60caps brahmi. They have associated 2 and subunits medicine 9 minutes buy brahmi with american express, which form a disulfide-linked transmembrane glycoprotein complex treatment effect definition purchase brahmi in india, and subunits, which are intracellular. The auxiliary subunits of Ca2 channels are not related in primary structure to the Na channel subunits. Only the principal subunits of the Na, Ca2 or K channels are required for function (Noda et al. However, co-expression of the auxiliary subunits increases the level of expression and modifies the voltagedependent gating, conferring more physiologically correct functional properties on the expressed channels (Isom et al. These results indicate that the principal subunits of the voltage-gated ion channels are functionally autonomous, but the auxiliary subunits improve expression and localization and modulate physiological properties. The Shaker mutation in Drosophila causes flies to shake when under ether anesthesia and is accompanied by loss of a specific K current in the nerve and muscle of the mutant flies. The K channel protein is analogous to one of the homologous domains of Na or Ca2 channels (Jan & Jan, 1997) and functions as a tetramer of four separate subunits, analogous to the structure of Na and Ca2 channels. Like the Na channels and the Ca2 channels, the K channels have auxiliary subunits, which include intracellularly located subunits as well as minK or minKrelated subunits that have a single transmembrane segment (Jan & Jan, 1997; Pongs, 1999). Much is known about the structural determinants of the ion selectivity filter and pore Which amino acid sequences are involved in forming the ion selectivity filter and pore Insight into this question first came from studies of the amino acid residues required for binding of tetrodotoxin, which blocks the Na channel ion selectivity filter at the outer mouth of the pore. Site-directed mutagenesis experiments showed that pairs of amino acid residues required for high-affinity tetrodotoxin binding are located in analogous positions in all four domains near the carboxyl ends of the short membrane-re-entrant segments between transmembrane -helices S5 and S6 (Terlau et al. Six of these eight residues are negatively charged and may interact with permeant ions as they approach and move through the channel. Parallel results implicated these same regions of the K channel in determining ion selectivity and conductance (Miller, 1990). These results led to the idea that these segments, often called the P loops, form the ion selectivity filter. The three-dimensional structure of the pore formed from the S5 and S6 segments and the intervening P loop was elegantly determined by X-ray crystallography of a bacterial K channel (Doyle et al. Bold lines represent the polypeptide chains of each subunit, with length approximately proportional to the number of amino acid residues. The remainder of the polypeptide chain is illustrated as a bold line, with the length of each segment approximately proportional to the length of its amino acid sequence. The P loops are cradled in this structure to form the narrow ion selectivity filter at the extracellular end of the pore. This remarkable structure elucidates the molecular basis for the formation of a transmembrane pore and suggests a mechanism for ion conduction (see below). In contrast, the structure of a distantly related bacterial K channel (Jiang et al. This conformational change appears to open the pore at its intracellular end by splaying open the bundle of inner pore helices. Mutational studies of Na channels support this pore-opening model because replacement of the conserved glycine with proline, which strongly favors a bend in the -helix, also strongly favors pore opening and greatly slows closure (Zhao et al. Analysis of crystals shows that four K ions can interact with the backbone carbonyl groups of the amino acid residues that form the ion selectivity filter. In one cycle of outward K conductance, K ions occupy sites 1 and 3 (orange), shift to sites 2 and 4 (gray), and then the K ion in site 4 moves into the extracellular space while a new K ion occupies site 1 and the K ion in site 2 moves to site 3, reestablishing the initial state. The figure illustrates a complete pore formed from the S5 (yellow) and S6 (red) transmembrane segments plus the P loop between them (orange) from four subunits of the channel. For clarity, only a single voltage sensor from one subunit of the channel is illustrated with its four transmembrane segments. Three additional voltage sensors would be symmetrically located to the right of the pore, behind it, and in front of it. The S4 segment of the voltage sensor is illustrated in green with the four positively charged arginine residues (R1-R4) that serve as gating charges superimposed as blue balls. The S1 (purple) and S2 (light blue) segments are illustrated as cylinders, and a key negatively charged residue in the S2 segment (E1) is represented as a red ball. This model of the closed state is derived from structural modeling (Yarov-Yarovoy et al. Its pore is closed by the straight conformation of the S6 helices, and its S4 segment is drawn inward such that the R1 gating charge is interacting with the key negatively charged residue E1. In this inward position, the S4 segment pushes on the pore and keeps the S6 segments straight, thereby keeping the pore closed. The model of this state of the channel is derived directly from the X-ray crystal structure (Yarov-Yarovoy et al. A unique feature of this structure is the connection of the voltage sensor on the left to the pore-forming module that is in the front of the pore through the S4-S5 linker (purple). Surprisingly, the voltage sensor makes its most intimate contacts with the pore-forming module of the adjacent subunit in clockwise direction as viewed from the extracellular side of the membrane. It is possible that this interwoven arrangement of the four subunits allows them to gate the pore simultaneously. The K ion in site 4 would dissociate into the extracellular space, the K ion in site 2 would move to site 3, and another K ion from the intracellular space would bind to site 1. In this way, the pore would remain occupied by two ions, during steady outward conduction. The aromatic and hydrophobic side chains of these amino acids contact the aromatic and substituted amino groups of the drug molecules and hold them in the receptor site, where they block ion movement through the pore. Voltage-dependent activation requires moving charges Structural models for voltage-dependent gating of ion channels must identify the voltage-sensors or gating charges. The S4 segments of the homologous domains have been proposed as voltage sensors (Catterall, 1986; Guy & Conti, 1990). These segments, which are conserved among Na, Ca2 and K channels, consist of repeated triplets of two hydrophobic amino acids followed by a positively charged residue. In the -helical configuration, these segments would form a spiral of positive charge across the membrane, a structure that is well suited for transmembrane movement of gating charge. The positive charges are thought to be neutralized by negative charges in the nearby S2 and S3 segments. Neutralization of positive charges results in progressive reduction of the steepness of voltage-dependent gating and of the apparent gating charge, as expected if indeed the S4 segments are the voltage sensors. At the resting membrane potential, the force of the electric field would pull the positive charges inward. Depolarization would abolish this force and allow an outward movement of the S4 helix. This outward movement has been detected in clever experiments that measure the movement of chemically reactive cysteine residues substituted for the native amino acids in S4 by analyzing the functional effects of specific chemical reactions at those substituted cysteines or the fluorescence of chemical probes located there (Bezanilla, 2000; Yang et al. This movement of the S4 helix is proposed to initiate a more general conformational change in each domain. After conformational changes have occurred in all four domains, the transmembrane pore can open and conduct ions. The structure determined by X-ray crystallography captured the activated state of the voltage sensor and the open state of the pore. Molecular modeling methods have been used to predict the structure of the resting state. By comparing the predicted structure of the resting state to the experimentally determined structure of the activated state, one can visualize the movement of the voltage sensor in response to depolarization of the membrane. The gating charges in the voltage sensor (blue balls) are in an outward position in this activated state structure, as revealed by the interactions observed between R3, R4 and the key negative charge E1. The three-dimensional structure of the resting state has not been determined by X-ray crystallography. The difficulty in determining the structure of the resting state using this technique may be caused by its voltage dependence-the resting state is only observed in an excitable cell at the resting membrane potential of 70 mV to 90 mV, and there is not an equivalent membrane potential in a protein crystal. A model of the resting state has therefore been developed using protein modeling methods, based on the structure of the activated state shown here, the structure of the closed pore of the KcsA channel. The model illustrates the pore in a closed conformation, formed by straightening of the S6 segments, and the voltage sensor in a resting conformation. This inward movement of the S4 segment of the voltage sensor moves the position of the S4-S5 linker (purple) and forces closure of the pore. The model of the resting state is approximate and will likely be revised when its structure is determined by X-ray crystallography, if that is possible. From these two structural models, one can visualize the steps in the gating of a voltage-gated ion channel. In the closed state, the negative internal membrane potential of 70 mV to 90 mV pulls the S4 gating charges inward by electrostatic force. The inward position of the S4 segment exerts a force on the S4-S5 linker, straightens the S6 segment, and closes the pore at its inner mouth. When the cell is depolarized, the electrostatic force pulling the S4 segment is relieved. In response to the change in electrostatic force, the S4 segment moves outward with each positive gating charge interacting with the negatively charged amino acid E1 in turn to ease their movement through the voltage sensor. When the R3 and R4 gating charges reach E1, the outward force on the S4-S5 linker is sufficient to pull on the pore-forming module and bend the S6 segment, resulting in opening of the pore at its intracellular end. Once the pore is open, the fast inactivation mechanism is engaged and the inactivation gate closes. This evolving structural view is still a minimal mechanism of voltage-dependent gating of an ion channel, and many details remain to be added to this picture in future research. The fast inactivation gate is on the inside Shortly after opening, many voltage-gated ion channels inactivate. The inactivation process of Na channels can be prevented by treatment of the intracellular surface of the channel I. Consistent with this mechanism, synthetic peptides whose amino acid sequences correspond to that of the inactivation particle region can restore inactivation to channel mutants whose N-terminus has been removed. The mechanisms of inactivation of Na and K channels are similar in that in each case hydrophobic amino acid residues seem to mediate binding of an inactivation particle to the intracellular mouth of the pore. It is likely that the hinged-lid mechanism of Na channel inactivation evolved from the ball-and-chain mechanism of K channels. Experiments in progress in many laboratories are beginning to reveal the meaning of this exceptional ion channel diversity. Any one of the four can bind to the intracellular mouth of the open channel and inactivate it. Na channels are primarily a single family There are 10 human genes encoding voltage-gated Na channels (Table 4-2), and at least 9 of the 10 encode members of a single family (NaV1. These Na channels are expressed in different tissues and cells, but their function is almost always to initiate action potentials in response to membrane depolarization. A single cluster of three hydrophobic residues in this intracellular loop is required for fast inactivation (West, Patton, Scheuer et al. Mutation of a single phenylalanine in the center of this motif nearly completely blocks fast inactivation of the channel. The cluster of hydrophobic residues may bind to the intracellular mouth of the pore like a latch to keep the channel inactivated. A detailed model of K channel inactivation has been derived from mutagenesis experiments on the original Shaker K channels from Drosophila (Armstrong, 2007; Hoshi et al. The N-terminal of the K channel serves as an inactivation particle and both charged and hydrophobic residues are involved. The inflow of Ca2 can assist in depolarizing cells, but it also performs an important messenger role. The entering Ca2 may activate exocytosis (secretion), contraction, gating of other channels, ciliary reorientation, metabolic pathways, gene expression, etc. Indeed, whenever an electrical message activates any non-electrical event, a change of the intracellular free Ca2 concentration acts as an intermediary. Genes that encode voltage-gated Ca2 channels (Table 4-2) are grouped in three subfamilies that have distinct functions. The CaV2 subfamily conducts N-, P/Q-, and R-type Ca2 currents and is particularly concentrated in nerve terminals where a Ca2 influx is required for fast release of chemical neurotransmitters (see Ch. The CaV3 subfamily conducts T-type Ca currents that are activated at negative membrane potentials and are transient. These channels are important in repetitively firing cells, like the sinoatrial nodal cells that serve as pacemakers in the heart and the neurons in the thalamus that generate sleep rhythms. This division of Ca2 channels is ancient-the worm Caenorhabditis elegans has a single member of each of these Ca2 channel subfamilies. Evidently, specialization of Ca2 signaling is crucial for even simple nervous systems. This has an important regulatory influence on the resting membrane potential in many neurons. A third type of K channel, K2P, has a structure similar to two fused Kir subunits, and only two K2P subunits are required to form a pore (Table 4-2) (Goldstein et al. These channels are often called leak channels or open rectifiers because they are continuously open. Like the Kir channels they are important in setting the resting membrane potential. There are many families of K channels K channels have many different roles in cells. For example, in neurons they terminate the action potential by repolarizing cells, set the resting membrane potential by dominating the resting membrane conductance, determine the length and frequency of bursts of action potentials, and respond to neurotransmitters by opening or closing and causing prolonged changes in membrane potential (Hille, 2001). These channels are regulated by a combination of voltage, G proteins and intracellular second messengers.

During axonal growth or regeneration medicine ball order 60 caps brahmi fast delivery, the expression of specific tubulin genes is upregulated medicine 3601 buy brahmi master card. Properties of slow axonal transport suggest molecular mechanisms Information about molecular mechanisms underlying slow axonal transport is relatively limited medicinebg 60 caps brahmi visa. The macroscopic transport velocity rates measured by radiolabeling experiments should not be taken to reflect maximum rates of the motors involved 911 treatment center buy cheap brahmi online. As with mitochondrial transport symptoms ringworm order discount brahmi line, the net rate velocity of slow component proteins reflects both the rate of actual movement and the fraction of a time interval that a structure is moving (Brady medications qt prolongation purchase brahmi us, 2000). The large size and elongated shape of cytoskeletal structures and their potential for many interactions means that net displacements are discontinuous. Other studies permitted visualization of microtubules nucleated at the microtubule organizing center and being translocated toward the cell periphery. As discussed below, there are still questions about the specific motors and mechanisms underlying these movements. Like membrane proteins, cytoplasmic and cytoskeletal proteins are differentially distributed in neurons and glia. Progress has been made toward identification of targeting mechanisms and some general principles have begun to emerge. Since cytoplasmic constituents move only in the anterograde direction, a key mechanism for targeting of cytoplasmic and cytoskeletal proteins appears to be differential metabolism (Brady, 1993). Proteins with slow degradative rates in the terminal would accumulate and reach a higher steady-state concentration. Thus, alteration of degradation rates for a protein can change the rate of accumulation for that protein. For example, some protease inhibitors cause the appearance of neurofilament rings in affected presynaptic terminals (Roots, 1983). Although slow axonal transport of cytoskeletal proteins has received the most attention, all other cytoplasmic proteins must be delivered to specific neuronal compartments of the neuron as well. Many of these have been defined as part of the "cytosol" or soluble fraction that results from biochemical fractionation. However, in pulse-chase radiolabel studies, soluble proteins move down the axon as regularly and systematically as cytoskeletal proteins. Again, this coherent transport of hundreds of different polypeptides appears consistent with the Structural Hypothesis and indicates a higher level of organization of cytoplasmic proteins than has been traditionally assumed (Lasek & Brady, 1982). Such organization is likely necessary to facilitate interactions with motor proteins and targeting mechanisms and to assure a reliable delivery of all required proteins to the axon at appropriate stoichometries. Myosins had been purified from nervous tissue, but no clear functions were established. The pharmacology and biochemistry of fast axonal transport created a picture of organelle transport distinct from muscle contraction or flagellar beating. Moreover, the biochemical properties of fast transport were inconsistent with both myosin and dynein (Brady et al. Both anterograde and retrograde moving organelles freeze in place on microtubules, and "pearls on a string" structures became apparent. The polypeptide composition of this new motor molecule was soon defined and it was christened kinesin (Brady et al. This discovery raised the possibility of other novel motor molecules and soon molecular biology techniques allowed the discovery of additional classes of molecular motors (Aizawa et al. The proliferation of motor types has transformed our understanding of cellular motility. With all mouse and human genes identified, it is currently known that each class of molecular motor proteins corresponds to large protein families with diverse cellular functions (Miki et al. Finally, the elusive cytoplasmic version of dynein was identified and a multigene family of flagellar and cytoplasmic dyneins defined (Asai & Wilkes, 2004). Members of a given motor protein family share significant homology in their motor domains with the defining member (kinesin, cytoplasmic dynein or myosin), but they also contain unique protein domains that are specialized for interaction with different cargoes or differential regulation (Hirokawa et al. This large number of motor proteins may reflect the number of cellular functions that require force generation or movement, ranging from mitosis to morphogenesis to transport of vesicles. In this chapter, we focus on major motor proteins known to be important for axonal transport or neuronal function, starting with conventional kinesin. Kinesins mediate anterograde fast axonal transport in a variety of cell types Since their discovery, much has been learned about the biochemical, pharmacological and molecular properties of kinesins (Brady & Sperry, 1995; Hirokawa et al. Conventional kinesin is the most abundant member of the kinesin superfamily in vertebrates and is widely distributed in neuronal and non-neuronal cells. Structural studies have shown that kinesin is a rod-shaped protein approximately 80 nm long, with two globular heads connected to a fanlike tail by a long stalk. High-resolution electron microscopic immunolocalization of kinesin subunits and molecular genetic studies both indicate that kinesin heavy chains are arranged in parallel with their amino terminals forming the heads and much of the stalk (Hirokawa et al. A large body of evidence implicates conventional kinesin as a motor molecule for fast axonal transport. Finally, reduction of kinesin heavy chain levels using antisense oligonucleotides and gene deletion studies also implicate conventional kinesin in axonal transport processes (Amaratunga et al. In addition to its role in fast axonal transport and related phenomena in non-neuronal cells, conventional kinesin appears to be involved in constitutive recycling of membranes from the Golgi to the endoplasmic reticulum. For example, the nuclear membrane, membranes of the Golgi complex and the plasma membrane all appear to lack conventional kinesin (Hirokawa et al. However, neither this selectivity nor the molecular basis for binding of kinesin and other motors to membranes are well understood. In addition, biochemical fractionation studies showed differential association of kinesin-1s with specific organelles (Deboer et al. Current evidence suggests that the different combination of subunits may produce functionally diverse forms of conventional kinesin and allow transport of different types of organelles in mature neurons (Deboer et al. These issues raise concerns about the physiological significance of many candidate receptor proteins identified to date. Additional work is needed to establish the precise functional role of each conventional kinesin subunit in this process. Multiple members of the kinesin superfamily are expressed in the nervous system Kinesin has been purified and cloned from many species, including Drosophila, squid, sea urchin, chicken, rat, and human. Both heavy and light chain subunits of conventional kinesin are highly conserved throughout. However, once the sequence of the kinesin motor domain was available, related proteins with homology only in the motor domain began to be identified. A careful analysis of kinesin superfamily sequences from many species led to the definition of a standardized kinesin nomenclature for 15 defined families of kinesins (Lawrence et al. Kinesin-2 family members have been implicated in assembly and maintenance of cilia and flagella and mutations in these motors can lead to sensory defects and polycystic kidney disease (Scholey, 2003). Kinesin-2 motors are heterotrimers with two related heavy chain subunits and a larger accessory subunit. Kinesin-3 family members were proposed as a synaptic vesicle motor because kinesin-3 mutants in the nematode C. The extent to which these kinesins reflect unique transport mechanisms rather than functional redundancy within the kinesin family is not known. For example, members of the kinesin-13 family have been implicated in both mitotic spindle function and in axonal membrane transport. Although kinesins were the last family of motor proteins to be discovered, the kinesin family has proven to be remarkably diverse. Fifteen distinct subfamilies in the kinesin family have been identified, all with homology in their motor domain (Lawrence et al. Within a subfamily, however, the more extensive sequence similarities are presumed to reflect related functions. At present, many questions remain about the function of these various motors in the nervous system. Identification of the cytoplasmic form of dynein in nervous tissue came as an indirect result of the discovery of kinesin. This discovery led to purification and characterization of brain cytoplasmic dynein (Paschal et al. As with the kinesins, dynein heavy chains are a multigene family with multiple flagellar and cytoplasmic dynein genes (Asai & Wilkes, 2004). At present, dynein genes are grouped as members of either flagellar or cytoplasmic dynein subfamilies. The three intermediate (74 kDa), four light intermediate (55 kDa) and a variable number of light chains present in dyneins may also have flagellar and cytoplasmic forms. The two or more cytoplasmic dynein heavy chain genes could be involved in different cellular functions, but much dynein functional diversity may be due to its many associated polypeptides (Susalka & Pfister, 2000). The intermediate and light chains of cytoplasmic dynein are thought to be important both for regulation and for interactions with specific cellular structures (Brill & Pfister, 2000). In addition, a second protein complex known as dynactin copurifies with cytoplasmic dynein under some conditions (Schroer, 2004). The dynactin complex is similar in size to dynein and contains multiple subunits that include p150Glued, dynamitin, an actin-related protein, and two actin capping polypeptides, among others. The p150Glued polypeptide interacts with both dynein intermediate chains and the actin related subunits. Dynamitin may play a role in the binding of cytoplasmic dynein to different types of cargo. Finally, the actin related protein (Arp1) forms a short filament that may include actin as well as actin-capping proteins. This short filament may interact with both p150Glued and components of the membrane cytoskeleton like spectrin. Dynactin may mediate cytoplasmic dynein binding to selected cargoes, including the Golgi complex and the membrane cytoskeleton. The wide range of functions associated with cytoplasmic dynein is matched by its complexity and its ability to interact with accessory factors (Susalka & Pfister, 2000). Additional proposed functions include a role in mitosis and in anchoring and localizing the Golgi complex. A number of studies have implicated cytoplasmic dynein as playing a role in retrograde axonal transport (Brady, 1991; Hirokawa, 1998). In the nervous system, the most frequent role proposed for dynein is a motor for retrograde axonal transport, but its properties are also consistent with a motor for slow axonal transport (Ahmad et al. The ability of dynactin to interact with both cytoplasmic dynein and the membrane cytoskeleton suggests a model in which dynactin links dynein to the membrane cytoskeleton, providing an anchor for dynein-mediated movement of axonal microtubules (Ahmad et al. Some anchoring role for the membrane-associated cytoskeleton in the mechanisms of slow axonal transport is likely, since neurons require interaction with a solid substrate for neurite growth. As observed for conventional kinesin, phosphorylation-based regulatory mechanisms for cytoplasmic dynein have been documented in neurons (Morfini et al. Different classes of myosin are important for neuronal function Myosins are remarkably diverse in structure and function. To date, 15 subfamilies of myosin have been defined by sequence homologies (Kalhammer & Bahler, 2000). The brain is an abundant source of non-muscle myosins and one of the earliest studied. Despite their abundance and variety, the roles of myosins in neural tissues have only recently begun to be defined (Bridgman, 2009; Brown & Bridgman, 2004). Myosin I is a singleheaded myosin with a short tail that uses calmodulin as a light chain (Kalhammer & Bahler, 2000). In many cell types it has been implicated in both endocytosis and exocytosis, so it may play an important role in delivery and recycling of receptors. Myosin I is enriched in microvilli and may also be involved in some aspects of growth cone motility, along with myosins from other subfamilies. The myosin I family has also been implicated in mechanotransduction by the stereocilia of hair cells in the inner ear and vestibular apparatus. A myosin I isoform, myosin I, has been localized to the tips of stereocilia, where it appears to mediate sensory adaptation by opening and closing the stretch-activated calcium channel (see Chapter 53). Two other myosin types have been implicated in hearing and vestibular function (Libby & Steel, 2000). Another myosin type that plays a role in nervous tissue is myosin V (Kalhammer & Bahler, 2000). Of the myosins identified in brain, myosin I and V are the strongest candidates to act as organelle motors, and myosin V has been reported in association with vesicles purified from squid axoplasm. Mice carrying the mutant dilute allele show defects in the movement of pigment granules, and this results in dilution of their coat color.

Growth hormone and parathyroid hormone stimulate intestinal calcium absorption in aged female rats medications with sulfa order line brahmi. Modulation of intestinal vitamin D receptor by ovariectomy medicine 524 discount brahmi 60caps online, estrogen and growth hormone symptoms ringworm cheap 60 caps brahmi amex. The role of insulin-like growth factor I in age-related changes in calcium homeostasis in men treatment norovirus purchase brahmi cheap. Immunological and biological evidence for a stanniocalcin-like hormone in human kidney symptoms synonym order 60 caps brahmi with mastercard. Overexpression of human stanniocalcin affects growth and reproduction in transgenic mice medicine queen mary buy brahmi 60 caps on-line. Stanniocalcin: a novel protein regulating calcium and phosphate transport across mammalian intestine. Regulation by 1alpha,25-dihydroxyvitamin D(3) of expression of stanniocalcin messages in the rat kidney and ovary. Recent advances in the renal-skeletal-gut axis that controls phosphate homeostasis. Calcium and phosphorus balance in extremely low birthweight infants in the first six weeks of life. Chapter 70 Molecular Mechanisms of Intestinal Transport of Calcium, Phosphate, and Magnesium 1915 245. Intestinal phosphate transport in spontaneously hypertensive rats and genetically matched controls. Phosphate transport in pig proximal small intestines during postnatal development: lack of modulation by calcitriol. Intestinal phosphate absorption and the effect of vitamin D: a comparison of rats with mice. Phosphate transport across rat jejunum: influence of sodium, pH, and 1,25-dihydroxyvitamin D3. Effects of potassium ions and sodium ions on membrane potential of epithelial cells in rat duodenum. Effect of pH on phosphate transport into intestinal brush-border membrane vesicles. Molecular cloning, functional expression, tissue distribution, and in situ hybridization of the renal sodium phosphate (Na/P(i)) transporter in the control and hypophosphatemic mouse. Cloning and functional characterization of a sodium-dependent phosphate transporter expressed in human lung and small intestine. Phosphonoformic acid blunts adaptive response of renal and intestinal Pi transport. Inhibition of human intestinal brush border membrane vesicle Na-dependent phosphate uptake by phosphophloretin derivatives. Molecular cloning and hormonal regulation of PiT-1, a sodium-dependent phosphate cotransporter from rat parathyroid glands. Cell-surface receptors for gibbon ape leukemia virus and amphotropic murine retrovirus are inducible sodiumdependent phosphate symporters. Regulation of rat intestinal Na-dependent phosphate transporters by dietary phosphate. Identification of a novel function of PiT1 critical for cell proliferation and independent of its phosphate transport activity. Phosphate transport across the basolateral membrane from rat kidney cortex: sodium-dependence Regulation of intestinal Na-dependent phosphate co-transporters by a low-phosphate diet and 1,25-dihydroxyvitamin D3. Intestinal Na-P(i) cotransporter adaptation to dietary P(i) content in vitamin D receptor null mice. Sodium-dependent phosphate uptake in the jejunum is post-transcriptionally regulated in pigs fed a low-phosphorus diet and is independent of dietary calcium concentration. Differential response of enterocytes to vitamin D during embryonic development: induction of intestinal inorganic phosphate, D-glucose and calcium uptake. Regulation of Na-dependent phosphate influx across the mucosal border of duodenum by 1,25-dihydroxycholecalciferol. Vitamin D-induced phosphate transport in intestinal brush border membrane vesicles. Regulation of Na-Pi cotransport by 1,25-dihydroxyvitamin D3 in rabbit duodenal brushborder membrane. The effects of metabolic acidosis on jejunal phosphate and glucose transport in weanling rats. Chapter 70 Molecular Mechanisms of Intestinal Transport of Calcium, Phosphate, and Magnesium 1917 314. Regulation of phosphate homeostasis by the phosphatonins and other novel mediators. Fibroblast growth factor 7: an inhibitor of phosphate transport derived from oncogenic osteomalacia-causing tumors. Inhibition of intestinal sodium-dependent inorganic phosphate transport by fibroblast growth factor 23. Effect of experimental human magnesium depletion on parathyroid hormone secretion and 1,25-dihydroxyvitamin D metabolism. Neurological manifestations of magnesium deficiency in infantile gastroenteritis and malnutrition. Reduction of dietary magnesium by only 50% in the rat disrupts bone and mineral metabolism. Transient receptor potential melastatin 6 and 7 channels, magnesium transport, and vascular biology: implications in hypertension. Potassium, magnesium, and electrolyte imbalance and complications in disease management. Magnesium absorption in human subjects from leafy vegetables, intrinsically labeled with stable 26 Mg. Apparent absorption and retention of Ca, Cu, Mg, Mn, and Zn from a diet containing bran. Promotive effects of resistant maltodextrin on apparent absorption of calcium, magnesium, iron and zinc in rats. Ileal pH and apparent absorption of magnesium in rats fed on diets containing either lactose or lactulose. The effect of a high intake of calcium on magnesium metabolism in normal subjects and patients with chronic renal failure. Jejunal and ileal adaptation to alterations in dietary calcium: changes in calcium and magnesium absorption and pathogenetic role of parathyroid hormone and 1,25-dihydroxyvitamin D. Magnesium absorption: mechanisms and the influence of vitamin D, calcium and phosphate. Characterization of Mg2 transport in brush border membrane vesicles of rabbit ileum studied with mag-fura-2. Uptake of (28)Mg by duodenal and jejunal brush border membrane vesicles in the rat. Results in normal subjects, patients with chronic renal disease, and patients with absorptive hypercalciuria. Effect of dietary calcium and phosphorus levels on the utilization of iron, copper, and zinc by adult males. Cellular-mediated and diffusive magnesium transport across the descending colon of the rat. Studies in primary hypomagnesaemia: evidence for defective carrier-mediated small intestinal transport of magnesium. In vitro studies on the transport of magnesium across the intestinal wall of the rat. Chapter 70 Molecular Mechanisms of Intestinal Transport of Calcium, Phosphate, and Magnesium 1919 391. Deletion of Trpm7 disrupts embryonic development and thymopoiesis without altering Mg2 homeostasis. Reconstituted amiloride-inhibited sodium transporter from rabbit kidney medulla is responsible for Na-H exchange. Characterization of the Na-dependent Mg2 transport in sheep ruminal epithelial cells. The epithelial Mg2 channel transient receptor potential melastatin 6 is regulated by dietary Mg2 content and estrogens. Iron is an essential nutrient as well as a toxicant that must be precisely managed. As such, mammals have developed sophisticated regulatory mechanisms that govern iron intake, storage, recycling, and use. Sufficient iron is necessary to support a number of critical physiological functions including binding to and distributing oxygen to body tissues, regulation of cell growth and differentiation, electron transfer reactions, control of gene expression, and cellular respiration. Iron can be found in four types of proteins where it serves a variety of important functions. These include the following protein classes: (1) iron-containing proteins with no enzymatic function, (2) iron-sulfur proteins, (3) heme-containing proteins, and (4) iron-dependent proteins that do not contain iron-sulfur clusters or heme. Iron is involved in energy metabolism via its role in single electron transfer reactions in ironsulfur enzymes. In the third type of iron-containing protein, iron incorporated into heme participates in a variety of electron transfer reactions in association with various cofactors. Proteins in the final category include those that transiently bind iron and facilitate its movement across the plasma membrane and intracellular membranes. The non-redundant role of iron in these proteins, as well as many others not listed here, exemplifies the importance of iron in mammalian physiology. During iron-deficient and hypoxic conditions, however, when hepcidin production is very low, additional regulatory mechanisms are invoked to regulate intestinal iron absorption. This process, however, is perturbed in a number of disease states in which control of iron absorption is dysregulated with pathological consequences. Decades-old investigations of body iron turnover demonstrated that humans have a limited capacity to excrete iron,3 so the overall control of body iron content must be achieved at the point of absorption. The daily intake of iron is finely tuned to replace the small amounts lost through the exfoliation of skin and gastrointestinal cells and lost in bile and urine. In adult males, this represents approximately 1 mg of iron per day, while human females absorb 1. Although its essentiality is well recognized, body iron levels must be tightly controlled, as excess free iron can be deleterious and no active excretory mechanisms exist in mammals. Furthermore, although some species are able to excrete greater quantities of iron than humans, the same basic regulatory schemes that have been Physiology of the Gastrointestinal Tract, Two Volume Set. Absorption of dietary iron by the duodenum and proximal jejunum is depicted as well as iron delivery to tissues and cells of the body. Small amounts of dietary iron are absorbed daily and passive iron losses more or less match these, although no regulated excretory processes exist. A larger amount of iron is recycled internally each day, deriving from the breakdown of senescent red blood cells by macrophages of the reticuloendothelial system. Most recycled iron is destined for the bone marrow for the production of hemoglobin in new erythrocytes. The liver produces the iron regulatory peptide hormone hepcidin in response to increased body iron stores, infection, and inflammation. Hepcidin decreases circulating iron levels by inhibiting iron export from intestinal epithelial cells, macrophages, and hepatocytes. Anatomically, iron is absorbed predominantly in the proximal small bowel, specifically across the epithelial cell layer of the duodenum and proximal jejunum, where absorption is restricted to the mature enterocytes on the upper half of the villus. If iron stores are replete, the bulk of absorbed iron will be stored within ferritin and later lost when that enterocyte is shed from the villus tip. Two adjacent, fully differentiated enterocytes are depicted showing the major proteins responsible for intestinal iron transport. Alternative sources of dietary iron are shown above the enterocyte to the right, including heme, lactoferrin, and ferritin. The entry and processing pathways for ferritin and lactoferrin are not understood in detail, but in either case, iron appears to be able to enter cells associated with these molecules. Also depicted are two mechanisms that regulate the expression of genes related to intestinal iron homeostasis. Each of these steps in iron absorption and related regulatory mechanisms will be considered in detail in the following sections. Iron homeostasis in undifferentiated enterocytes of the intestinal crypts is quite different from their mature counterparts. These immature epithelial cells are not specialized for vectorial iron (or nutrient) transport and act more like a generic cell. They are rapidly growing and dividing, so they have a high demand for iron, which they absorb as Tf-bound iron from the serosal side unlike mature enterocytes, which get their iron from the dietary components on the luminal side. Both TfR1-dependent and -independent diferric Tf uptake have been demonstrated in crypt enterocytes. Diseases associated with reduced iron absorption are much less common, and this may attest to the essentiality of the metal. Occasionally refractory anemias are described that appear to result from defective iron absorption, but only one of these has been attributed to an intestinal iron transport-related molecule. Finally, there is accumulating evidence that during the development of iron deficiency there is morphological adaptation of the intestinal mucosa to increase the effective absorptive area37 and upregulate the capacity of the intestine to absorb iron. Thus in hemolytic anemia, villous enterocytes from lower portions of the villus participate in absorption,38 villous size is increased during pregnancy,39 and during iron deficiency absorption occurs in more distal gut segments. The brief overview of the importance of iron as a nutrient and the basics of the intestinal transport process presented earlier will be greatly expanded upon in subsequent sections.

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