Homeostatic regulation mechanism of spontaneous firing determines glutamate responsiveness in the midbrain dopamine neurons

Autonomous tonic firing of the midbrain dopamine neuron is essential for maintenance of ambient dopamine level in the brain, in which intracellular Ca²⁺ concentration ([Ca²⁺]c) plays a complex but pivotal role. However, little is known about Ca²⁺ signals by which dopamine neurons maintain an optimum spontaneous firing rate. In the midbrain dopamine neurons, we here show that spontaneous firing evoked [Ca²⁺]c changes in a phasic manner in the dendritic region but a tonic manner in the soma. Tonic levels of somatic [Ca²⁺]c strictly tallied with spontaneous firing rates. However, manipulatory raising or lowering of [Ca²⁺]c with caged compounds from the resting firing state proportionally suppressed or raised spontaneous firing rate, respectively, suggesting presence of the homeostatic regulation mechanism for spontaneous firing rate via tonic [Ca²⁺]c changes of the soma. More importantly, abolition of this homeostatic regulation mechanism significantly exaggerated the responses of tonic firings and high-frequency phasic discharges to glutamate. Therefore, we conclude that this Ca²⁺-dependent homeostatic regulation mechanism is responsible for not only maintaining optimum rate of spontaneous firing, but also proper responses to glutamate. Perturbation of this mechanism could cause dopamine neurons to be more vulnerable to glutamate and Ca²⁺ toxicities.     

Homeostatic regulation of blood neutrophil counts

Blood neutrophil counts are determined by the differentiation and proliferation of precursor cells, the release of mature neutrophils from the bone marrow, margination, trafficking and transmigration through the endothelial lining, neutrophil apoptosis, and uptake by phagocytes. This brief review summarizes the regulation of blood neutrophil counts, which is in part controlled by G-CSF, IL-17, and IL-23. Neutrophils are retained in the bone marrow through interaction of CXCL12 with its receptor CXCR4. The relevance of this mechanism is illustrated by rare diseases in which disrupting the desensitization of CXCR4 results in failure to release mature neutrophils from bone marrow. Although blood neutrophil numbers in inbred mouse strains and individual human subjects are tightly controlled, their large variation among outbred populations suggests genetic factors. One example is benign ethnic neutropenia, which is found in some African Americans. Reduced and elevated neutrophil counts, even within the normal range, are associated with excess all-cause mortality.     

Homeostatic and circadian regulation of cognitive performance

Cognitive processes are crucial for human performance. Basic cognitive processes, such as attention, working memory, and executive functions, show homeostatic (time awake, sleep deprivation) and circadian (time of day) variations. Each of these cognitive processes includes several components, which contribute sequentially to the homeostatic and circadian modulation of performance. Sudden (lapses) and gradual changes in cognitive performance occur with sleep deprivation or with time of day. The time course of human cognitive processes throughout the day is relevant to the programming of different human activities. The lowest level of cognitive performance occurs during nighttime and early in the morning, a better level occurs around noon, and even higher levels occur during afternoon and evening hours. However, this time course can be modulated by conditions such as chronotype, sleep deprivation, sleep disorders or medication that affects the central nervous system.     

Homeostatic regulation of sleep in arrhythmic Siberian hamsters

Sleep is regulated by independent yet interacting circadian and homeostatic processes. The present study used a novel approach to study sleep homeostasis in the absence of circadian influences by exposing Siberian hamsters to a simple phase delay of the photocycle to make them arrhythmic. Because these hamsters lacked any circadian organization, their sleep homeostasis could be studied in the absence of circadian interactions. Control animals retained circadian rhythmicity after the phase shift and re-entrained to the phase-shifted photocycle. These animals displayed robust daily sleep-wake rhythms with consolidated sleep during the light phase beginning about 1 h after light onset. This marked sleep-wake pattern was circadian in that it persisted in constant darkness. The distribution of sleep in the arrhythmic hamsters over 24 h was similar to that in the light phase of rhythmic animals. Therefore, daily sleep amounts were higher in arrhythmic animals compared with rhythmic ones. During 2- and 6-h sleep deprivations (SD), it was more difficult to keep arrhythmic hamsters awake than it was for rhythmic hamsters. Because the arrhythmic animals obtained more non-rapid eye movement sleep (NREMS) during the SD, they showed a diminished compensatory response in NREMS EEG slow-wave activity during recovery sleep. When amounts of sleep during the SD were taken into account, there were no differences in sleep homeostasis between experimental and control hamsters. Thus loss of circadian control did not alter the homeostatic response to SD. This supports the view that circadian and homeostatic influences on sleep regulation are independent processes.     

Homeostatic regulation of glutamate release in response to depolarization

Proper nervous system function requires a balance between excitation and inhibition. Systems of homeostasis may have evolved in neurons to help maintain or restore balance between excitation and inhibition, presumably because excessive excitation can cause dysfunction and cell death. This article reviews evidence for homeostatic mechanisms within the hippocampus that lead to differential regulation of glutamate and gamma-aminobutyric acid release in response to conditions of excess depolarization. We recently found differential effects on glutamate release at the level of action potential coupling to transmitter release, vesicular release probability, and vesicle availability. Such differential regulation may help to prevent excitotoxicity and runaway excitation.     

In search of nonribosomal nucleolar protein function and regulation

The life of the nucleolus has proven to be more colorful and multifaceted than had been envisioned a decade ago. A large number of proteins found in this subnuclear compartment have no identifiable tie either to the ribosome biosynthetic pathway or to the other newly established activities occurring within the nucleolus. The questions of how and why these proteins end up in this subnuclear compartment remain unanswered and are the focus of intense current interest. This review discusses our thoughts on the discovery of nonribosomal proteins in the nucleolus.     

Redox regulation and reaction mechanism of human cystathionine-beta-synthase: a PLP-dependent hemesensor protein

Cystathionine beta-synthase in mammals lies at a pivotal crossroad in methionine metabolism directing flux toward cysteine synthesis and catabolism. The enzyme exhibits a modular organization and complex regulation. It catalyzes the beta-replacement of the hydroxyl group of serine with the thiolate of homocysteine and is unique in being the only known pyridoxal phosphate-dependent enzyme that also contains heme b as a cofactor. The heme functions as a sensor and modulates enzyme activity in response to redox change and to CO binding. Mutations in this enzyme are the single most common cause of hereditary hyperhomocysteinemia. Elucidation of the crystal structure of a truncated and highly active form of the human enzyme containing the heme- and pyridoxal phosphate binding domains has afforded a structural perspective on mechanistic and mutation analysis studies. The C-terminal regulatory domain containing two CBS motifs exerts intrasteric regulation and binds the allosteric activator, S-adenosylmethionine. Studies with mammalian cells in culture as well as with animal models have unraveled multiple layers of regulation of cystathionine beta-synthase in response to redox perturbations and reveal the important role of this enzyme in glutathione-dependent redox homestasis. This review discusses the recent advances in our understanding of the structure, mechanism, and regulation of cystathionine beta-synthase from the perspective of its physiological function, focusing on the clinically relevant human enzyme.     

Capping protein: new insights into mechanism and regulation

Temporal and spatial control of the actin cytoskeleton are crucial for a range of eukaryotic cellular processes. Capping protein (CP), a ubiquitous highly conserved heterodimer, tightly caps the barbed (fast-growing) end of the actin filament and is an important component in the assembly of various actin structures, including the dynamic branched filament network at the leading edge of motile cells. New research into the molecular mechanism of how CP interacts with the actin filament in vitro and the function of CP in vivo, including discoveries of novel interactions of CP with other proteins, has greatly enhanced our understanding of the role of CP in regulating the actin cytoskeleton.     

The mechanism of protein kinase C regulation

Protein kinase C (PKC) is a family of serine/threonine protein kinases that plays a central role in transducing extracellular signals into a variety of intracellular responses ranging from cell proliferation to apoptosis. Nine PKC genes have been identified in the human genome, which encode 10 proteins. Each member of this protein kinase family displays distinct biochemical characteristics and is enriched in different cellular and subcellular locations. Activation of PKC has been implicated in the regulation of cell growth and differentiation. This review summarizes works of the past years in the field of PKC biochemistry that covers regulation and activation mechanism of different PKC isoforms.     

Uteroferrin: A protein in search of a function

Uteroferrin, a purple-colored, iron-containing acid phosphatase, with many of the properties of a lysosomal hydrolase, transports iron from the mother to the conceptus in pregnant pigs. Uteroferrin, however, is but one member of what may be a broad class of iron-containing phosphatases with unusual spectral properties which result from a novel type of di-iron active site. The biological function of uteroferrin is unknown. We argue here that the in vivo function of uteroferrin, despite its undoubted ability to act as a potent acid phosphatase, is that of a transplacental iron transporter.     

The regulation of N-acetylglutamate synthetase in rat liver by protein intake

Urea cycle enzymes are subjected to regulation by dietary proteins. We have shown that this is also the case for N-acetylglutamate synthetase (EC 2.3.1.1.) (NAGS). Four different groups (n = 7) of male Wistar rats received either a low protein (8.7%) or a high (32% and 51%) protein diet and a control diet of 17% protein. The NAGS-activity in the liver, assayed after 15 days of feeding the different diets, increased from 25 +/- 7 (controls, 17% protein) to 31 +/- 5 (32% protein) and to 52 +/- 17 (51% protein) nmoles.min-1.g-1 wet weight. It decreased in the group with low protein diet (8.7%) to 5 +/- 3. The ratio of the arginine stimulated to the unstimulated enzyme activity remained constant over the range of protein intake. Similar changes were observed for carbamylphosphate synthetase, ornithine carbamyltransferase and arginase. As it is known for these enzymes adaptive mechanisms in relation to variations in dietary protein consumption also could be demonstrated for the enzyme NAGS.     

Homeostatic regulation of intestinal villous epithelia by B lymphocytes

The epithelial cell of the small intestine is one of the most rapidly regenerating cells in the body. However, the cellular mechanism and biological significance underlying this rapid regeneration remain elusive. In this study we examined the intestinal epithelia of mutant mice that lack B and/or T cells and those of normal littermates. The absence of B cells in Ig mu-chain mutant mice or B and T cells in recombination-activating gene (RAG)-2(-/-) as well as SCID mutant mice was associated with a marked acceleration of epithelial cell turnover and an up-regulation of the expression of MHC class II molecules. No such effects were observed in T cell-deficient TCR-delta and -beta double-mutant mice. As far as the goblet cells of villous epithelium are concerned, absolute numbers of them remained the same among these mutant mice that have no B and/or T cells. Alymphoplasia (aly/aly) mutant mice that lacked Peyer's patches and Ig-producing cells in the lamina propria, but harbored a large number of intestinal mucosal T cells, also displayed a significant acceleration of epithelial cell turnover and, to some extent, up-regulated expression of MHC class II molecules. Notably, the accelerated epithelial cell turnover was not observed and returned to normalcy in the Ig mu-chain mutant mice that had been given antibiotic-containing water. These findings indicate that B cells down-regulate the generation and differentiation of intestinal epithelial cells in the normal wild-type condition and suggest that enteric microorganisms are implicated in the accelerated generation of epithelial cells in mice that have no B cells.