Showing papers in "Annual Review of Physiology in 2002"

Short-Term Synaptic Plasticity

Abstract: ▪ Abstract Synaptic transmission is a dynamic process. Postsynaptic responses wax and wane as presynaptic activity evolves. This prominent characteristic of chemical synaptic transmission is a crucial determinant of the response properties of synapses and, in turn, of the stimulus properties selected by neural networks and of the patterns of activity generated by those networks. This review focuses on synaptic changes that result from prior activity in the synapse under study, and is restricted to short-term effects that last for at most a few minutes. Forms of synaptic enhancement, such as facilitation, augmentation, and post-tetanic potentiation, are usually attributed to effects of a residual elevation in presynaptic [Ca2+]i, acting on one or more molecular targets that appear to be distinct from the secretory trigger responsible for fast exocytosis and phasic release of transmitter to single action potentials. We discuss the evidence for this hypothesis, and the origins of the different kinetic phases...

Structure and function of dendritic spines.

Abstract: Spines are neuronal protrusions, each of which receives input typically from one excitatory synapse. They contain neurotransmitter receptors, organelles, and signaling systems essential for synaptic function and plasticity. Numerous brain disorders are associated with abnormal dendritic spines. Spine formation, plasticity, and maintenance depend on synaptic activity and can be modulated by sensory experience. Studies of compartmentalization have shown that spines serve primarily as biochemical, rather than electrical, compartments. In particular, recent work has highlighted that spines are highly specialized compartments for rapid large-amplitude Ca(2+) signals underlying the induction of synaptic plasticity.

Aromatase—A Brief Overview

Abstract: There is growing awareness that androgens and estrogens have general metabolic roles that are not directly involved in reproductive processes. These include actions on vascular function, lipid and carbohydrate metabolism, as well as bone mineralization and epiphyseal closure in both sexes. In postmenopausal women, as in men, estrogen is no longer solely an endocrine factor but instead is produced in a number of extragonadal sites and acts locally at these sites in a paracrine and intracrine fashion. These sites include breast, bone, vasculature, and brain. Within these sites, aromatase action can generate high levels of estradiol locally without significantly affecting circulating levels. Circulating C19 steroid precursors are essential substrates for extragonadal estrogen synthesis. The levels of these androgenic precursors decline markedly with advancing age in women, possible from the mid-to-late reproductive years. This may be a fundamental reason why women are at increased risk for bone mineral loss and fracture, and possibly decline of cognitive function, compared with men. Aromatase expression in these various sites is under the control of tissue-specific promotors regulated by different cohorts of transcription factors. Thus in principle, it should be possible to develop selective aromatase modulators (SAMs) that block aromatase expression, for example, in breast, but allow unimpaired estrogen synthesis in other tissues such as bone.

Mycosporine-Like Amino Acids and Related Gadusols: Biosynthesis, Accumulation, and UV-Protective Functions in Aquatic Organisms

Abstract: Organisms living in clear, shallow water are exposed to the damaging wavelengths of solar ultraviolet radiation (UVR) coincident with the longer wavelengths of photosynthetically available radiation (PAR) also necessary for vision. With the general exception of bacteria, taxonomically diverse marine and freshwater organisms have evolved the capacity to synthesize or accumulate UV-absorbing mycosporine-like amino acids (MAAs), presumably for protection against environmental UVR. This review highlights the evidence for this UV-protective role while also considering other attributed functions, including reproductive and osmotic regulation and vision. Probing the regulation and biosynthesis of MAAs provides insight to the physiological evolution and utility of UV protection and of biochemically associated antioxidant defenses.

G proteins and phototransduction.

Abstract: Phototransduction is the process by which a photon of light captured by a molecule of visual pigment generates an electrical response in a photoreceptor cell. Vertebrate rod phototransduction is one of the best-studied G protein signaling pathways. In this pathway the photoreceptor-specific G protein, transducin, mediates between the visual pigment, rhodopsin, and the effector enzyme, cGMP phosphodiesterase. This review focuses on two quantitative features of G protein signaling in phototransduction: signal amplification and response timing. We examine how the interplay between the mechanisms that contribute to amplification and those that govern termination of G protein activity determine the speed and the sensitivity of the cellular response to light.

Regulation of Endothelial Nitric Oxide Synthase: Location, Location, Location

Abstract: ▪ Abstract Endothelial nitric oxide synthase (eNOS) is expressed in vascular endothelium, airway epithelium, and certain other cell types where it generates the key signaling molecule nitric oxide (NO). Diminished NO availability contributes to systemic and pulmonary hypertension, atherosclerosis, and airway dysfunction. Complex mechanisms underly the cell specificity of eNOS expression, and co- and post-translational processing leads to trafficking of the enzyme to plasma membrane caveolae. Within caveolae, eNOS is the downstream target member of a signaling complex in which it is functionally linked to both typical G protein-coupled receptors and less typical receptors such as estrogen receptor (ER) α and the high-density lipoprotein receptor SR-BI displaying novel actions. This compartmentalization facilitates dynamic protein-protein interactions and calcium- and phosphorylation-dependent signal transduction events that modify eNOS activity. Further understanding of these mechanisms will enable us to t...

Bile Salt Transporters

Abstract: Bile salts are the major organic solutes in bile and undergo extensive enterohepatic circulation. Hepatocellular bile salt uptake is mediated predominantly by the Na(+)-taurocholate cotransport proteins Ntcp (rodents) and NTCP (humans) and by the Na(+)-independent organic anion-transporting polypeptides Oatp1, Oatp2, and Oatp4 (rodents) and OATP-C (humans). After diffusion (bound by intracellular bile salt-binding proteins) to the canalicular membrane, monoanionic bile salts are secreted into bile canaliculi by the bile salt export pump Bsep (rodents) or BSEP (humans). Both belong to the ATP-binding cassette (ABC) transporter superfamily. Dianionic conjugated bile salts are secreted into bile by the multidrug-resistance-associated proteins Mrp2/MRP2. In bile ductules, a minor portion of protonated bile acids and monomeric bile salts are reabsorbed by non-ionic diffusion and the apical sodium-dependent bile salt transporter Asbt/ASBT, transported back into the periductular capillary plexus by Mrp3/MRP3 [and/or a truncated form of Asbt (tAsbt)], and subjected to cholehepatic shunting. The major portion of biliary bile salts is aggregated into mixed micelles and transported into the intestine, where they are reabsorbed by apical Oatp3, the apical sodium-dependent bile salt transporter (ASBT), cytosolic intestinal bile acid-binding protein (IBABP), and basolateral Mrp3/MRP3 and tAsbt. Transcriptional and posttranscriptional regulation of these enterohepatic bile salt transporters is closely related to the regulation of lipid and cholesterol homeostasis. Furthermore, defective expression and function of bile salt transporters have been recognized as important causes for various cholestatic liver diseases.

Fatty Acid Oxidation Disorders

Abstract: ▪ Abstract Genetic disorders of mitochondrial fatty acid β-oxidation have been recognized within the last 20 years as important causes of morbidity and mortality, highlighting the physiological significance of fatty acids as an energy source. Although the mammalian mitochondrial fatty acid-oxidizing system was recognized at the beginning of the last century, our understanding of its exact nature remains incomplete, and new components are being identified frequently. Originally described as a four-step enzymatic process located exclusively in the mitochondrial matrix, we now recognize that long-chain-specific enzymes are bound to the inner mitochondrial membrane, and some enzymes are expressed in a tissue-specific manner. Much of our new knowledge of fatty acid metabolism has come from the study of patients who were diagnosed with single-gene autosomal recessive defects, a situation that seems to be further evolving with the emergence of phenotypes determined by combinations of multiple genetic and environ...

Ovulation: new dimensions and new regulators of the inflammatory-like response.

Abstract: Ovulation is a complex process that is initiated by the lutenizing hormone surge and is controlled by the temporal and spatial expression of specific genes. This review focuses on recent endocrine, biochemical, and genetic information that has been derived largely from the identification of new genes that are expressed in the ovary, and from knowledge gained by the targeted deletion of genes that appear to impact the ovulation process. Two main areas are described in most detail. First, because mutant mouse models indicate that appropriate formation of the cumulus matrix is essential for successful ovulation, genes expressed in the cumulus cells and those that control cumulus expansion are discussed. Second, because mice null for the progesterone receptor fail to ovulate and are ideal models for dissecting the critical events downstream of progesterone receptor, genes expressed in mural granulosa cells that regulate the expression of novel proteases are described.

Cardiac Ion Channels

Abstract: The normal electrophysiologic behavior of the heart is determined by ordered propagation of excitatory stimuli that result in rapid depolarization and slow repolarization, thereby generating action potentials in individual myocytes. Abnormalities of impulse generation, propagation, or the duration and configuration of individual cardiac action potentials form the basis of disorders of cardiac rhythm, a continuing major public health problem for which available drugs are incompletetly effective and often dangerous. The integrated activity of specific ionic currents generates action potentials, and the genes whose expression results in the molecular components underlying individual ion currents in heart have been cloned. This review discusses these new tools and how their application to the problem of arrhythmias is generating new mechanistic insights to identify patients at risk for this condition and developing improved antiarrhythmic therapies.

PROLACTIN: The New Biology of an Old Hormone

Abstract: Prolactin (PRL) is a paradoxical hormone. Historically known as the pituitary hormone of lactation, it has had attributed to it more than 300 separate actions, which can be correlated to the quasi-ubiquitous distribution of its receptor. Meanwhile, PRL-related knockout models have mainly highlighted its irreplaceable role in functions of lactation and reproduction, which suggests that most of its other reported target tissues are presumably modulated by, rather than strictly dependent on, PRL. The multiplicity of PRL actions in animals is in direct opposition to the paucity of arguments that suggest its involvement in human pathophysiology other than effects on reproduction. Although many experimental data argue for a role of PRL in the progression of some tumors, such as breast and prostate cancers, drugs lowering circulating PRL levels are ineffective. This observation opens new avenues for research into the understanding of whether local production of PRL is involved in tumor growth and, if so, how extrapituitary PRL synthesis is regulated. Finally, the physiological relevance of PRL variants, such as the antiangiogenic 16K-like PRL fragments, needs to be elucidated. This review is aimed at critically discussing how these recent findings have renewed the manner in which PRL should be considered as a multifunctional hormone.

Epithelial Sodium Channel and the Control of Sodium Balance: Interaction Between Genetic and Environmental Factors

Abstract: ▪ Abstract The epithelial sodium channel (ENaC) expressed in aldosterone-responsive epithelial cells of the kidney and colon plays a critical role in the control of sodium balance, blood volume, and blood pressure. In lung, ENaC has a distinct role in controlling the ionic composition of the air-liquid interface and thus the rate of mucociliary transport. Loss-of-function mutations in ENaC cause a severe salt-wasting syndrome in human pseudohypoaldosteronism type 1 (PHA-1). Gain-of-function mutations in ENaC β and γ subunits cause pseudoaldosteronism (Liddle's syndrome), a severe form of salt-sensitive hypertension. This review discusses genetically defined forms of a salt sensitivity and salt resistance in human monogenic diseases and in animal models mimicking PHA-1 or Liddle's syndrome. The complex interaction between genetic factors (ENaC mutations) and the risk factor (salt intake) can now be studied experimentally. The role of single-nucleotide polymorphisms (SNPs) in determining salt sensitivity or...

Calmodulin as an Ion Channel Subunit

Abstract: ▪ Abstract A surprising variety of ion channels found in a wide range of species from Homo to Paramecium use calmodulin (CaM) as their constitutive or dissociable Ca2+-sensing subunits. The list includes voltage-gated Ca2+ channels, various Ca2+- or ligand-gated channels, Trp family channels, and even the Ca2+-induced Ca2+ release channels from organelles. Our understanding of CaM chemistry and its relation to enzymes has been instructive in channel research, yet the intense study of CaM regulation of ion channels has also revealed unexpected CaM chemistry. The findings on CaM channel interactions have indicated the existence of secondary interaction sites in addition to the primary CaM-binding peptides and the functional differences between the N- and C-lobes of CaM. The study of CaM in channel biology will figure into our understanding on how this uniform, universal, vital, and ubiquitous Ca2+ decoder coordinates the myriad local and global cell physiological transients.

Gm-CSF regulates pulmonary surfactant homeostasis and alveolar macrophage-mediated innate host defense.

Abstract: ▪ Abstract Recent studies in transgenic mice have revealed important insights into the roles of GM-CSF in regulation of surfactant homeostasis and lung host defense. Interruption of the GM-CSF signaling pathway by targeted ablation of the GM-CSF gene or its receptor (GM−/− or GM Rβc−/− mice, respectively) resulted in pulmonary alveolar proteinosis (PAP) but no hematologic abnormalities. Alveolar macrophages from GM−/− mice have reduced capacity for surfactant catabolism, cell adhesion, phagocytosis, bacterial killing, Toll-receptor signaling, and expression of various pathogen-associated molecular pattern recognition receptors, suggesting arrest at an early stage of differentiation. PAP and abnormalities of alveolar macrophage function were corrected by local expression of GM-CSF in the lung, and expression of the transcription factor PU.1 in alveolar macrophages of GM−/− mice rescued most defects. Recently, a strong association of auto-antibodies to GM-CSF or GM-CSF receptor gene mutations with PAP has i...

β-Defensins in Lung Host Defense

Abstract: ▪ Abstract Host defenses at the mucosal surface of the airways evolved to present many layers of protection against inhaled microbes. Normally, the intrapulmonary airways are sterile. Airway secretions contain numerous factors with antimicrobial activity that contribute to innate defenses. Many protein and peptide components exert bacteriostatic or bacteriocidal effects against a wide variety of organisms and may act in synergistic or additive combinations. The β-defensins are a relatively recently described family of peptide antimicrobials that are widely expressed at mucosal surfaces, including airway and submucosal gland epithelia. These small cationic peptides are products of individual genes that exhibit broad-spectrum activity against bacteria, fungi, and some enveloped viruses. Their expression in airway epithelia may be constitutive or inducible by bacterial products or pro-inflammatory cytokines. β-defensins also act as chemokines for adaptive immune cells, including immature dendritic cells and ...

Molecular Mechanism of Active Ca2+ Reabsorption in the Distal Nephron

Abstract: The identification of the epithelial Ca(2+) channel (ECaC) complements the group of Ca(2+) transport proteins including calbindin-D28K, Na(+)/Ca(2+) exchanger and plasma membrane Ca(2+)-ATPase, which are co-expressed in 1,25(OH)2D3- responsive nephron segments. ECaC constitutes the rate-limiting apical entry step in the process of active transcellular Ca(2+) transport and belongs to a superfamily of Ca(2+) channels that includes the vanilloid receptor and transient receptor potential channels. This new Ca(2+) channel consists of six transmembrane-spanning domains, including a pore-forming hydrophobic stretch between domain 5 and 6. The C- and N-terminal tails contain several conserved regulatory sites, implying that the channel function is modulated by regulatory proteins. The distinctive functional properties of ECaC include a constitutively activated Ca(2+) permeability, a high selectivity for Ca(2+), hyperpolarization-stimulated and Ca(2+)-dependent feedback regulation of channel activity, and 1,25(OH)2D3-induced gene activation. This review covers the distinctive properties of this new highly Ca(2+)-selective channel and highlights the implications for active transcellular Ca(2+) reabsorption in health and disease.

Molecular Aspects of Renal Anionic Drug Transport

Abstract: Multiple organic anion transporters in the proximal tubule of the kidney are involved in the secretion of drugs, toxic compounds, and their metabolites. Many of these compounds are potentially hazardous on accumulation, and it is therefore not surprising that the proximal tubule is also an important target for toxicity. In the past few years, considerable progress has been made in the cloning of these transporters and their functional characterization following heterologous expression. Members of the organic anion transporter (OAT), organic anion transporting polypeptide (OATP), multidrug resistance protein (MRP), sodium-phosphate transporter (NPT), and peptide transporter (PEPT) families have been identified in the kidney. In this review, we summarize our current knowledge on their localization, molecular and functional characteristics, and substrate and inhibitor specificity. A major challenge for the future will be to understand how these transporters work in concert to accomplish the renal secretion of specific anionic substrates.

Human and murine phenotypes associated with defects in cation-chloride cotransport.

Abstract: ▪ Abstract The diuretic-sensitive cotransport of cations with chloride is mediated by the cation-chloride cotransporters, a large gene family encompassing a total of seven Na-Cl, Na-K-2Cl, and K-Cl cotransporters, in addition to two related transporters of unknown function. The cation-chloride cotransporters perform a wide variety of physiological roles and differ dramatically in patterns of tissue expression and cellular localization. The renal-specific Na-Cl cotransporter (NCC) and Na-K-2Cl cotransporter (NKCC2) are involved in Gitelman and Bartter syndrome, respectively, autosomal recessive forms of metabolic alkalosis. The associated phenotypes due to loss-of-function mutations in NCC and NKCC2 are consistent, in part, with their functional roles in the distal convoluted tubule and thick ascending limb, respectively. Other cation-chloride cotransporters are positional candidates for Mendelian human disorders, and the K-Cl cotransporter KCC3, in particular, may be involved in degenerative peripheral ne...

Molecular pathogenesis of lung cancer.

Abstract: Lung cancer is the most common cause of cancer death in the United States, killing more than 156,000 people every year. In the past two decades, significant progress has been made in understanding the molecular and cellular pathogenesis of lung cancer. Abnormalities of proto-oncogenes, genetic and epigenetic changes of tumor suppressor genes, the role of angiogenesis in the multistage development of lung cancer, as well as detection of molecular abnormalities in preinvasive respiratory lesions, have recently come into focus. Efforts are ongoing to translate these findings into new clinical strategies for risk assessment, chemoprevention, early diagnosis, treatment selection, and prognosis and to provide new targets and methods of treatment for lung cancer patients. All these strategies should aid in reducing the number of newly diagnosed lung cancer cases and in increasing the survival and quality of life of patients with lung cancer.

Genetic diseases of acid-base transporters.

Abstract: ▪ Abstract Genetic disorders of acid-base transporters involve plasmalemmal and organellar transporters of H+, HCO3−, and Cl−. Autosomal-dominant and -recessive forms of distal renal tubular acidosis (dRTA) are caused by mutations in ion transporters of the acid-secreting Type A intercalated cell of the renal collecting duct. These include the AE1 Cl−/HCO3− exchanger of the basolateral membrane and at least two subunits of the apical membrane vacuolar (v)H+-ATPase, the V1 subunit B1 (associated with deafness) and the V0 subunit a4. Recessive proximal RTA with ocular disease arises from mutations in the electrogenic Na+-bicarbonate cotransporter NBC1 of the proximal tubular cell basolateral membrane. Recessive mixed proximal-distal RTA accompanied by osteopetrosis and mental retardation is associated with mutations in cytoplasmic carbonic anhydrase II. The metabolic alkalosis of congenital chloride-losing diarrhea is caused by mutations in the DRA Cl−/HCO3− exchanger of the ileocolonic apical membrane. Rec...

G proteins and olfactory signal transduction.

Abstract: ▪ Abstract The olfactory system sits at the interface of the environment and the nervous system and is responsible for correctly coding sensory information from thousands of odorous stimuli. Many theories existed regarding the signal transduction mechanism that mediates this difficult task. The discovery that odorant transduction utilizes a unique variation (a novel family of G protein–coupled receptors) based upon a very common theme (the G protein–coupled adenylyl cyclase cascade) to accomplish its vital task emphasized the power and versatility of this motif. We now must understand the downstream consequences of this cascade that regulates multiple second messengers and perhaps even gene transcription in response to the initial interaction of ligand with G protein–coupled receptor.

Mechanisms of Iron Accumulation in Hereditary Hemochromatosis

Abstract: Hereditary hemochromatosis (HH) is a common inborn error of iron metabolism characterized by excess dietary iron absorption and iron deposition in several tissues. Clinical consequences include hepatic failure, hepatocellular carcinoma, diabetes, cardiac failure, impotence, and arthritis. Despite the discovery of the mutation underlying most cases of HH, considerable uncertainty exists in the mechanism by which the normal gene product, HFE, regulates iron homeostasis. Knockout of the HFE gene clearly confers the HH phenotype on mice. However, studies on HFE expressed in cultured cells have not yet clarified the mechanism by which HFE mutations lead to increased dietary iron absorption. Recent discoveries suggest other genes, including a second transferrin receptor and the circulating peptide hepcidin, participate in a shared pathway with HFE in regulation of iron absorption. This review summarizes our current understanding of the relationship between iron stores and absorption and presents models to explain the dysregulated iron homeostasis in HH.

Hypoxia-Induced Anapyrexia: Implications and Putative Mediators

Abstract: ▪ Abstract Hypoxia elicits an array of compensatory responses in animals ranging from protozoa to mammals. Central among these responses is anapyrexia, the regulated decrease of body temperature. The importance of anapyrexia lies in the fact that it reduces oxygen consumption, increases the affinity of hemoglobin for oxygen, and blunts the energetically costly responses to hypoxia. The mechanisms of anapyrexia are of intense interest to physiologists. Several substances, among them lactate, adenosine, opioids, and nitric oxide, have been suggested as putative mediators of anapyrexia, and most appear to act in the central nervous system. Moreover, there is evidence that the drop in body temperature in response to hypoxia, unlike the ventilatory response to hypoxia, does not depend on the activation of peripheral chemoreceptors. The current knowledge of the mechanisms of hypoxia-induced anapyrexia are reviewed.

Intracellular transport mechanisms of signal transducers.

Abstract: Recent discoveries have revolutionized our conceptions of enzyme-substrate specificity in signal transduction pathways. Protein kinases A and C are localized to discreet subcellular regions, and this localization changes in an isozyme-specific manner upon activation, a process referred to as translocation. The mechanisms for translocation involve interactions of soluble kinases with membrane-bound anchor proteins that recognize individual kinase isoenzymes and their state of activation. Recently, modulation of kinase-anchor protein interactions has been used to specifically regulate, positively or negatively, the activity of C kinase isozymes. Also described in this review is a role for the Rab family of small G proteins in regulating subcellular protein trafficking. The pathophysiological significance of disrupted subcellular protein transport in cell signaling and the potential therapeutic utility of targeted regulation of these events are in the process of being characterized.

G proteins and pheromone signaling.

Abstract: All cells have the capacity to respond to chemical and sensory stimuli. Central to many such signaling pathways is the heterotrimeric G protein, which transmits a signal from cell surface receptors to intracellular effectors. Recent studies using the yeast Saccharomyces cerevisiae have produced important advances in our understanding of G protein activation and inactivation. This review focuses on the mechanisms by which G proteins transmit a signal from peptide pheromone receptors to the mating response in yeast and how mechanisms elucidated in yeast can provide insights to signaling events in more complex organisms.

Trafficking of canalicular ABC transporters in hepatocytes.

Abstract: ATP-binding cassette (ABC) transporters located in the hepatocyte canalicular membrane of mammalian liver are critical players in bile formation and detoxification. Although ABC transporters have been well characterized functionally, only recently have several canalicular ABC transporters been cloned and their molecular nature revealed. Subsequently, development of specific antibodies has permitted a detailed investigation of ABC transporter intrahepatic distribution under varying physiological conditions. It is now apparent that there is a complex array of ABC transporters in hepatocytes. ABC transporter molecules reside in intrahepatic compartments and are delivered to the canalicular domain following increased physiological demand to secrete bile. Insufficient amounts of ABC transporters in the bile canalicular membrane result in cholestasis (i.e., bile secretory failure). Therefore, elucidation of the intrahepatic pathways and regulation of ABC transporters may help to understand the cause of cholestasis at a molecular level and provide clues for novel therapies.

Potassium Channel Ontogeny

Abstract: Potassium channels are multi-subunit complexes, often composed of several polytopic membrane proteins and cytosolic proteins. The formation of these oligomeric structures, including both biogenesis and trafficking, is the subject of this review. The emphasis is on events in the endoplasmic reticulum (ER), particularly on how, where, and when K(+) channel polypeptides translocate and integrate into the bilayer, oligomerize and fold to form pore-forming units, and associate with auxiliary subunits to create the mature channel complex. Questions are raised with respect to the sequence of these events, when biogenic decisions are made, models for integration of K(+) channel transmembrane segments, crosstalk between the cell surface and ER, and recognition of compatible partner subunits. Also considered are determinants of subunit composition and stoichiometry, their consequence for trafficking, mechanisms for ER retention and export, and sequence motifs that direct channels to the cell surface. It is these mechanistic issues that govern the differential distributions of K(+) conductances at the cell surface, and hence the electrical activity of cells and tissues underlying both the physiology and pathophysiology of an organism.

A Hundred Years of Sodium Pumping

Abstract: This article gives a history of the evidence (a) that animal cell membranes contain pumps that expel sodium ions in exchange for potassium ions; (b) that the pump derives energy from the hydrolysis of ATP; (c) that it is thermodynamically reversible-artificially steep transmembrane ion gradients make it run backward synthesizing ATP from ADP and orthophosphate; (d) that its mechanism is a ping-pong one, in which phosphorylation of the pump by ATP is associated with an efflux of three sodium ions, and hydrolysis of the phosphoenzyme is associated with an influx of two potassium ions; (e) that each half of the working cycle involves both the transfer of a phosphate group and a conformational change-the phosphate transfer being associated with the occlusion of ions bound at one surface and the conformational change releasing the occluded ions at the opposite surface.

Molecular chaperones in the kidney.

Abstract: The normal milieu of the kidney includes hypoxia, large osmotic fluxes, and an enormous amount of fluid/solute reabsorption. Renal adaptation to these conditions requires a host of molecular chaperones that stabilize protein conformation, target nascent proteins to their final intracellular destination, and prevent protein aggregation. Under physiologic or pharmacologic stress, inducible molecular chaperones provide additional mechanisms for repairing or degrading non-native proteins and for inhibiting stress-induced apoptosis. In contrast to intracellular chaperones, chaperones present on the cell surface regulate the immune system and have cytokine-like effects. A diverse range of chaperones and chaperone functions provide the renal cell with an armamentarium of responses to improve the chances of survival.

The Renin Angiotensin System and Kidney Development

Abstract: When angiotensin II or AT1 receptor is experimentally inhibited during the perinatal period, either by pharmacological intervention or genetic manipulation, the kidney develops with profound structural abnormalities. Most prominent are hypertrophy of arterial vasculatures and atrophy of the papilla. Although the mechanism by which the vascular hypertrophy occurs remains unknown, study of the atrophic papilla gives us a new clue for understanding the physiological role of angiotensin. Mutant mice completely devoid of AT1 receptor fail to develop the renal pelvis and the ureteral peristaltic movement. Normally, angiotensin and AT1 receptor are transiently up-regulated around the renal outlet at birth. Thus angiotensin II induces the peristaltic machinery during the perinatal period in a timely fashion to accommodate the dramatic increase in urine production that occurs during the transition from intra- to extra-uterine life. Further studies revealed that in adult animals angiotensin augments the peristaltic movement when the urinary tract is partially obstructed, thereby protecting the kidney from hydronephrosis. This newly discovered function of angiotensin to protect kidney architecture at the time of urine outflow obstruction is reminiscent of its similar kidney structure-protecting function that is active during arterial blood flow obstruction.