The gastric HK-ATPase: structure, function, and inhibition

The gastric H,K-ATPase, a member of the P₂-type ATPase family, is the integral membrane protein responsible for gastric acid secretion. It is an α,β-heterodimeric enzyme that exchanges cytoplasmic hydronium with extracellular potassium. The catalytic α subunit has ten transmembrane segments with a cluster of intramembranal carboxylic amino acids located in the middle of the transmembrane segments TM4, TM5,TM6, and TM8. Comparison to the known structure of the SERCA pump, mutagenesis, and molecular modeling has identified these as constituents of the ion binding domain. The β subunit has one transmembrane segment with N terminus in cytoplasmic region. The extracellular domain of the β subunit contains six or seven N-linked glycosylation sites. N-glycosylation is important for the enzyme assembly, maturation, and sorting. The enzyme pumps acid by a series of conformational changes from an E₁ (ion site in) to an E₂ (ion site out) configuration following binding of MgATP and phosphorylation. Several experimental observations support the hypothesis that expulsion of the proton at 160 mM (pH 0.8) results from movement of lysine 791 into the ion binding site in the E₂P configuration. Potassium access from the lumen depends on activation of a K and Cl conductance via a KCNQ1/KCNE2 complex and Clic6. K movement through the luminal channel in E₂P is proposed to displace the lysine along with dephosphorylation to return the enzyme to the E₁ configuration. This enzyme is inhibited by the unique proton pump inhibitor class of drug, allowing therapy of acid-related diseases.     

A review: The agents and actions of sympathetic nerve and catecholamine inhibition of gastric mucosal function

The role of the sympathetic nerve supply to the gastric mucosa in gastric physiology is discussed. It is concluded that they are inhibitory to gastric acid secretion, mucosal blood flow, pepsin secretion, gastric oxygen consumption and that these nerves also decrease the serum gastrin concentration. Sympathetic nerve stimulation always reduces the mucosal blood flow and it is suggested therefore, that the inhibition of gastric secretion could be secondary to vasoconstriction mediated by noradrenaline release. The evidence for these conclusions is considered alongside the available histological evidence. It is concluded that the remaining hurdle is to place these phenomena within our knowledge of gastric physiology.     

The oxytocin receptor system: structure, function, and regulation

The neurohypophysial peptide oxytocin (OT) and OT-like hormones facilitate reproduction in all vertebrates at several levels. The major site of OT gene expression is the magnocellular neurons of the hypothalamic paraventricular and supraoptic nuclei. In response to a variety of stimuli such as suckling, parturition, or certain kinds of stress, the processed OT peptide is released from the posterior pituitary into the systemic circulation. Such stimuli also lead to an intranuclear release of OT. Moreover, oxytocinergic neurons display widespread projections throughout the central nervous system. However, OT is also synthesized in peripheral tissues, e.g., uterus, placenta, amnion, corpus luteum, testis, and heart. The OT receptor is a typical class I G protein-coupled receptor that is primarily coupled via G(q) proteins to phospholipase C-beta. The high-affinity receptor state requires both Mg(2+) and cholesterol, which probably function as allosteric modulators. The agonist-binding region of the receptor has been characterized by mutagenesis and molecular modeling and is different from the antagonist binding site. The function and physiological regulation of the OT system is strongly steroid dependent. However, this is, unexpectedly, only partially reflected by the promoter sequences in the OT receptor gene. The classical actions of OT are stimulation of uterine smooth muscle contraction during labor and milk ejection during lactation. While the essential role of OT for the milk let-down reflex has been confirmed in OT-deficient mice, OT's role in parturition is obviously more complex. Before the onset of labor, uterine sensitivity to OT markedly increases concomitant with a strong upregulation of OT receptors in the myometrium and, to a lesser extent, in the decidua where OT stimulates the release of PGF(2 alpha). Experiments with transgenic mice suggest that OT acts as a luteotrophic hormone opposing the luteolytic action of PGF(2 alpha). Thus, to initiate labor, it might be essential to generate sufficient PGF(2 alpha) to overcome the luteotrophic action of OT in late gestation. OT also plays an important role in many other reproduction-related functions, such as control of the estrous cycle length, follicle luteinization in the ovary, and ovarian steroidogenesis. In the male, OT is a potent stimulator of spontaneous erections in rats and is involved in ejaculation. OT receptors have also been identified in other tissues, including the kidney, heart, thymus, pancreas, and adipocytes. For example, in the rat, OT is a cardiovascular hormone acting in concert with atrial natriuretic peptide to induce natriuresis and kaliuresis. The central actions of OT range from the modulation of the neuroendocrine reflexes to the establishment of complex social and bonding behaviors related to the reproduction and care of the offspring. OT exerts potent antistress effects that may facilitate pair bonds. Overall, the regulation by gonadal and adrenal steroids is one of the most remarkable features of the OT system and is, unfortunately, the least understood. One has to conclude that the physiological regulation of the OT system will remain puzzling as long as the molecular mechanisms of genomic and nongenomic actions of steroids have not been clarified.     

The nuclear pore complex: structure, function, and dynamics

A full understanding of nucleocytoplasmic transport depends on knowledge of nuclear pore complex (NPC) structure, the functional roles of NPC components, their interactions during transport and dynamics during the cell cycle. NPC structure is conserved, flexible, and is not simply a tunnel between the nucleus and cytoplasm but appears to be actively involved in the transport process by a series of structural modifications. Transport through the NPC begins in either of its asymmetrical peripheral compartments that are both structurally reorganized during transport in different ways. The central compartment is composed of two symmetrical halves, and functions as a system of transiently open, discrete gates that is not believed to play a role in determining direction. Each NPC subunit has a specific morphology that corresponds to the functional role it plays. A complicated system of vertical and horizontal connections may allow one part of the NPC to transmit a signal to other parts, leading to an ordered series of conformational changes that drive translocation. High-resolution scanning electron microscopy has identified sequential stages of NPC assembly in vitro and revealed how the individual NPC components are assembled into a mature NPC. This review focuses on structural events during transport and on possible mechanisms of NPC assembly.     

The gap junction family: structure, function and chemistry

Summary Gap junctions are aggregates of transmembranous channels which bypass the extracellular space by transporting messenger molecules and ions from one cytoplasmic source to an adjacent cytoplasmic interior. The channels join the plasma membranes of adjacent cells by bridging the extracellular space between them. Thereby, cellular compartments which were once considered to be individual units are, in actuality, interconnected by a system of pathways which form a functional cellular syncytium. The evolutionary importance of a generalized intercellular communication system can be appreciated when one considers the widespread prevalence of gap junctions within animals of all multicellular phyla, and within almost all tissues of vertebrates. Only a few population of cells such as skeletal muscle cells (which are fused to form functional syncytia) and circulating blood cells are not equipped with gap junctions. This paper provides a brief review of the diverse structural, molecular and functional aspects of gap junctions as revealed by current research.     

The vascular pole of hepatocytes: structure, function and pathology

Structural and functional subdivision of the hepatocyte into a sinusoidal (vascular) zone, a lateral zone and a peri-canicular zone (adjacent to the bile canaliculi) highlights certain peculiarities of the vascular hepatocyte pole. In contrast to the total cytoplasm, this area is characterized by a high volume of mitochondria, altered peroxisome content, a high concentration of lipids and the absence of Golgi-apparatus. Of critical importance is the sinusoidal cell membrane: at birth, the hepatocyte of the rat bears some 1,000 microvilli, rising to 4,600 in the mature animal. The surface to volume ratio of this part of the cell is more than 250% of the overall cell ratio. The ectoplasmic area beneath it is of importance to the structural integrity and function of the cell membrane itself. Pathological changes such as formation of blebs, shedding of cytoplasm, detachment of portions of the vascular pole, emergence of phagocytic processes, production of atypical substances (i.e. amyloid precursors), are closely and interactively related to pathologic processes of other elements of this region (non-hepatocyte, space of Disse). The peri-sinusoidal functional complex, may have an importance for the pathology of the liver which has not been fully appreciated to date.     

The adrenergic mechanisms of the inhibition of the gastric acid-forming function in acute stress

It was demonstrated in experiments on Wistar rats that blockade of central adrenergic structures by thymopentin and beta-adrenergic receptors by inderal prevents stress inhibition of hydrochloric acid secretion. Normalization of the antioxidative protection of the stomach which prevents activation of the processes of free-radical oxidation in it plays an essential role in the mechanism of the stress-protective effect of adrenergic influences blockade on the gastric acid-producing function.     

The structure, regulation, and function of ZAP-70

Summary:  The tyrosine ZAP-70 (ζ-associated protein of 70 kDa) kinase plays a critical role in activating many downstream signal transduction pathways in T cells following T-cell receptor (TCR) engagement. The importance of ZAP-70 is evidenced by the severe combined immunodeficiency that occurs in ZAP-70-deficient mice and humans. In this review, we describe recent analyses of the ZAP-70 crystal structure, revealing a complex regulatory mechanism of ZAP-70 activity, the differential requirements for ZAP-70 and spleen tyrosine kinase (SyK) in early T-cell development, as well as the role of ZAP-70 in chronic lymphocytic leukemia and autoimmunity. Thus, the critical importance of ZAP-70 in TCR signaling and its predominantly T-cell-restricted expression pattern make ZAP-70 an attractive drug target for the inhibition of pathological T-cell responses in disease.     

The HLA system: structure and function.

The HLA system is the major histocompatibility system of man and was found through a search for blood group-like determinants on white blood cells that would be effective in matching for transplantation. The HLA system has its counterparts in other species of mammals, birds, and reptiles including the much studied H2 system of the mouse. The HLA system started from a series of antigens defined by a combination of relatively crude serology and genetics, supported by extensive statistical analysis. It has turned out to be a complex genetic region determining two major sets of cell surface products which mediate essential functional interactions between cells of the immune system, and so have a major role in the control of the immune response. Polymorphism in the HLA region is thus associated with a wide variety of diseases with an immune aetiology.     

The T4 molecule: function and structure

T4 antigen bearing T lymphocytes are central immunoregulatory cells which display helperlinducer functions, proliferate in response to antigen, control suppression and release lymphokines. In this review, Angus Dalgleish describes growing evidence that these different functions are carried out by phenotypically different subpopulations of T4-positive T cells, and discusses T4 as a putative receptor for class II MHC molecules and HTLV-III.     

Prolactin: structure, function, and regulation of secretion

Prolactin is a protein hormone of the anterior pituitary gland that was originally named for its ability to promote lactation in response to the suckling stimulus of hungry young mammals. We now know that prolactin is not as simple as originally described. Indeed, chemically, prolactin appears in a multiplicity of posttranslational forms ranging from size variants to chemical modifications such as phosphorylation or glycosylation. It is not only synthesized in the pituitary gland, as originally described, but also within the central nervous system, the immune system, the uterus and its associated tissues of conception, and even the mammary gland itself. Moreover, its biological actions are not limited solely to reproduction because it has been shown to control a variety of behaviors and even play a role in homeostasis. Prolactin-releasing stimuli not only include the nursing stimulus, but light, audition, olfaction, and stress can serve a stimulatory role. Finally, although it is well known that dopamine of hypothalamic origin provides inhibitory control over the secretion of prolactin, other factors within the brain, pituitary gland, and peripheral organs have been shown to inhibit or stimulate prolactin secretion as well. It is the purpose of this review to provide a comprehensive survey of our current understanding of prolactin's function and its regulation and to expose some of the controversies still existing.     

Eosinophil crystalloid granules: structure, function, and beyond

Eosinophils are granulocytes associated with host defense against parasitic helminths with allergic conditions and more recently, with immunoregulatory responses. Eosinophils are distinguished from leukocytes by their dominant population of cytoplasmic crystalloid (also termed secretory, specific, or secondary) granules that contain robust stores of diverse, preformed cationic proteins. Here, we provide an update on our knowledge about the unique and complex structure of human eosinophil crystalloid granules. We discuss their significance as rich sites of a variety of receptors and review our own recent research findings and those of others that highlight discoveries concerning the function of intracellular receptors and their potential implications in cell signaling. Special focus is provided on how eosinophils might use these intracellular receptors as mechanisms to secrete, selectively and rapidly, cytokines or chemokines and enable cell-free extracellular eosinophil granules to function as independent secretory structures. Potential roles of cell-free eosinophil granules as immune players in the absence of intact eosinophils will also be discussed.     

Neuronal nicotinic receptors: function,modulation and structure

In the present paper, we discuss the diversity of nicotinic receptors (nAChRs) expressed in hippocampal neurons and their functional properties. Three distinct types of whole-cell currents can be identified in hippocampal neurons by brief application of nicotinic agonists. These currents, which are referred to as types IA, II and III, were distinguished pharmacologically on the basis of their differential sensitivities to various nicotinic agonists and antagonists, and functionally on the basis of their rectification properties and rundown. Most of the hippocampal neurons show type IA current in response to nicotinic agonists, and the single channels that account for these currents in addition to having a very short open time and a high conductance, have a high Ca²⁺permeability and inactivate very fast. Based on the comparison of the properties of the nicotinic currents elicited in hippocampal neurons with those elicited by activation of nAChRs transiently expressed in oocytes, we have concluded that type IA currents may be subserved by α 7-bearing nAChRs, type II currents by α4β2 nAChRs, and type III currents by α3β4 nAChRs. Indeed,in-situhybridization shows that mRNAs coding for α7, α4 and β2 nAChR subunits are present in hippocampal neurons. These findings altogether have given new insights for the studies of neurophysiological processes and neuropathological conditions in which neuronal nAChRs may be implicated.