Presynaptic glutamate receptors: physiological functions and mechanisms of action

Glutamate acts on postsynaptic glutamate receptors to mediate excitatory communication between neurons. The discovery that additional presynaptic glutamate receptors can modulate neurotransmitter release has added complexity to the way we view glutamatergic synaptic transmission. Here we review evidence of a physiological role for presynaptic glutamate receptors in neurotransmitter release. We compare the physiological roles of ionotropic and metabotropic glutamate receptors in short- and long-term regulation of synaptic transmission. Furthermore, we discuss the physiological conditions that are necessary for their activation, the source of the glutamate that activates them, their mechanisms of action and their involvement in higher brain function.     

Peptides derived from the extracellular loop of receptors: structure, mechanisms of action and application in physiology and medicine

One of the main tasks of the peptide strategy, a new direction in modern biochemistry and physiology, is the creation of selective and effective regulators of hormonal signaling systems on the basis of the peptides corresponding to functionally important regions of signal proteins. At the last years the greatest interest is connected with peptides, derivatives of the extracellular loops of receptors of the serpentine type. With these peptides the molecular basis of interaction between receptors and their ligands are studied, the new approaches for construction and testing of highly selective agonists and antagonists are developed, the etiology and pathogenesis of diseases of human and animals induced by autoimmune reactions to the extracellular loops of receptors are investigated. It is shown that peptides corresponding to the extracellular loops of the receptors and the specific antibodies to them are capable to regulate the activity of hormonal signaling systems in vitro and in vivo and can be considered as functional probes for studying of physiological functions in the norm and pathology. In the review the data obtained during the last years concerning the structures, functions, mechanisms of action and practical application ofpeptides, derivatives of the extracellular loops of serpentine type receptors, are summarized and analyzed. The prospective of their use in fundamental biology and practical medicine are discussed.     

Angiotensin II receptors and mechanisms of action in adrenal glomerulosa cells

The plasma-membrane receptors, coupling mechanisms, and effector enzymes that mediate target-cell activation by angiotensin II (AII) have been characterized in rat and bovine adrenal glomerulosa cells. The AII holoreceptor is a glycoprotein of Mr approximately 125,000 under non-denaturing conditions. Photoaffinity labeling of AII receptors with azido-AII derivatives has shown size heterogeneity among the AII binding sites between species and target tissues, with Mr values of 55,000 to 79,000. Such variations in molecular size probably reflect differences in carbohydrate content of the individual receptor sites. The adrenal AII receptor, like that in other tissues, is coupled to the inhibitory guanine nucleotide inhibitory protein (Ni). However, studies with pertussis toxin have shown that stimulation of aldosterone production by AII is not mediated by Ni but by a pertussis-insensitive nucleotide regulatory protein of unidentified nature. Although Ni is not involved in the stimulatory action of AII on steroidogenesis, it does mediate the inhibitory effects of high concentrations of AII upon aldosterone production. The actions of AII on adrenal cortical function are thus regulated by at least two guanine nucleotide regulatory proteins that are selectively activated by increasing AII concentrations. The principal effector enzyme in AII action is phospholipase C, which is rapidly stimulated in rat and bovine glomerulosa after AII receptor activation. AII-induced breakdown of phosphatidylinositol bisphosphate (PIP2) and phosphatidylinositol phosphate (PIP) leads to formation of inositol 1,4,5-trisphosphate (IP3) and inositol 1,4-bisphosphate (IP2). These are metabolized predominantly to inositol-4-monophosphate, which serves as a marker of polyphosphoinositide breakdown, whereas inositol-1-phosphate is largely derived from phosphatidylinositol hydrolysis. The AII-stimulated glomerulosa cell also produces inositol 1,3,4-trisphosphate, a biologically inactive IP3 isomer formed from Ins-1,4,5-trisphosphate via inositol tetrakisphosphate (IP4) during ligand activation in several calcium-dependent target cells. The Ins-1,4,5-P3 formed during AII action binds with high affinity to specific intracellular receptors that have been characterized in the bovine adrenal gland and other AII target tissues, and may represent the sites through which IP3 causes calcium mobilization during the initiation of cellular responses.     

Nuclear positioning: mechanisms and functions

The nucleus is the largest organelle in the cell and its position is dynamically controlled in space and time, although the functional significance of this dynamic regulation is not always clear. Nuclear movements are mediated by the cytoskeleton which transmits pushing or pulling forces onto the nuclear envelope. Recent studies have shed light on the mechanisms regulating nuclear positioning inside the cell. While microtubules have been known for a long time to be key players in nuclear positioning, the actin and cytoplasmic intermediate filament cytoskeletons have been implicated in this function more recently and various molecular links between the nuclear envelope and cytoplasmic elements have been identified. In this review, we summarize the recent advances in our understanding of the molecular mechanisms involved in the regulation of nuclear localization in various animal cells and give an overview of the evidence suggesting a crucial role of nuclear positioning in cell polarity and physiology and the consequences of nuclear mispositioning in human pathologies.     

Serpentine type receptors and heterotrimeric G-proteins in yeasts: Structural-functional organization and molecular mechanisms of action

The signal systems of the yeasts Saccharomyces cerevisiae and Schizosaccharomyces pombe, coupled to heterotrimeric G-proteins and sensitive to pheromones and alimentary molecules, are prototypes of hormonal signal systems of the higher vertebrate animals and are widely used in studies on molecular mechanisms of their functioning. This review summarizes and analyzes data on structural-functional organization of the first two components of these systems—receptors of the serpentine type and heterotrimeric G-proteins; mechanisms of functional coupling of receptors and G-proteins both between each other and to other signal proteins are discussed. It has been shown that at the early stages of evolution of signaling systems, at the yeast level, various models of transduction of signals into the cell were tested; many of them differ essentially from the classic model of the three-component, G-protein-coupled signal system of the higher vertebrates.     

Sites and mechanisms of action of melatonin in mammals: the MT1 and MT2 receptors

The rhythmic secretion of melatonin by the pineal gland plays a key role in the synchronisation of circadian and seasonal functions with cyclic environmental variations. The biological effects of this neurohormone are relayed mainly by G-protein-coupled seven-transmembrane receptors. These receptors, known as MT1 and MT2, are present in a large number of central and peripheral structures in mammals, with considerable inter-species variations. However, only the suprachiasmatic nuclei of the hypothalamus, the site of the master circadian biological clock, and the pars tuberalis of the adenohypophysis contain melatonin receptors in the majority of species. Inhibition of the production of AMPc by a Gi/Go protein is one of the principal signalling pathways of the MT1 and MT2 receptors, although many other signal transduction pathways are also brought into play according to the cell type studied (PKC, Ca2+, K+ channels or GMPc in the case of MT2, etc.). Numerous factors or physiological stimuli are capable of influencing the number and functional status of the MT1 and MT2 receptors, such as melatonin, the photoperiod, the circadian clock or the phenomena of receptor dimerisation. Melatonin has numerous physiological effects for which the mechanisms of action and the specific role of the MT1 and MT2 receptors have not yet been clearly elucidated. However, selective pharmacological tools for each of the two receptor subtypes are currently being identified, notably in the Servier Group, for the purpose of furthering our knowledge of the functionality and physiological role of the MT1 and MT2 receptors in the central and peripheral structures.     

Antifungal agents: mechanisms of action

Clinical needs for novel antifungal agents have altered steadily with the rise and fall of AIDS-related mycoses, and the change in spectrum of fatal disseminated fungal infections that has accompanied changes in therapeutic immunosuppressive therapies. The search for new molecular targets for antifungals has generated considerable research using modern genomic approaches, so far without generating new agents for clinical use. Meanwhile, six new antifungal agents have just reached, or are approaching, the clinic. Three are new triazoles, with extremely broad antifungal spectra, and three are echinocandins, which inhibit synthesis of fungal cell wall polysaccharides--a new mode of action. In addition, the sordarins represent a novel class of agents that inhibit fungal protein synthesis. This review describes the targets and mechanisms of action of all classes of antifungal agents in clinical use or with clinical potential.