Roles of Ca2+ channels in physiological functions of mammalian central synapses were discussed from a system-oriented point of view. In the presynaptic terminals of the mammalian CNS so far studied, synaptic transmission is mediated by the subclass of Ca2+ channels designated as the Ntype (α1B channels) and/or by that designated as the P/Q-type (α1A channels). In some central synapses such as those between neocortical pyramidal neurons, synaptic transmission is presynaptically suppressed by various transmitter-modulators. Our electrophysiological data indicate that the receptors for amines, glutamate, GABA and adenosine co-exist on individual terminals, and they exert a common modulatory effect on synaptic transmission. Details of the intracellular cascade, i.e., G-protein and Ca2+ channel subtypes that are linked in this modulation, remain to be elucidated. Although the direct ‘membrane delimited’ action of G-proteins on Ca2+ channels is strongly suggested as a modulatory mechanism by the resemblance to the modulation observed in other neurons, the indirect second messenger pathways, however, may also be involved in the control of Ca2+ channels. Postsynaptically located Ca2+ channels are considered to play important roles in the regulation of neuronal excitability and synaptic plasticity. Individual dendritic spines apparently serve as a primary unit in an increase in Ca2+ level. This compartmentalized increase of Ca2+ seems essential for determining plastic changes of the synaptic efficacy in those particular spines. There is ample evidence indicating that the postsynaptic Ca2+ channels are involved in this Ca2+ transient. In order to understand the physiological significance of Ca2+ channels in CNS functions, further elucidation of channel subtypes, intracellular cascades of the modulator actions and characterization of the channel modifications will be essential.
Accumulating evidence indicate that various growth-related genes, growth factors and extracellular matrix components play a central role in the pathogenesis of cardiovascular and renal diseases by regulating cellular phenotype, growth and migration or promoting tissue fibrosis. Treatment of hypertensive rats with an angiotensin II type 1-receptor (AT1-receptor) antagonist normalizes cardiac phenotypic modulation and the increased fibrosis-related gene expressions in hypertrophied heart, leading to the improvement of cardiac dysfunction. The AT1-receptor antagonist can inhibit protooncogenes (c-fos, c-jun and Egr-1) and fibronectin gene expressions in rat balloon-injured artery, which is associated with the inhibition of neointima formation. Furthermore, the AT1-receptor antagonist prevents either the phenotypic modulation of glomerular mesangial cells or the increase in transforming growth factor-β1 expression in nephrosclerosis. Thus, the AT1-receptor antagonist in vivo potently inhibits the expression of growth-related gene and extracellular matrix and inhibits cellular phenotypic modulation. The AT1-receptor is responsible for the pathogenesis and development of cardiovascular and renal diseases.
Nerve growth factor (NGF) is a prototype of neurotrophin family neurotrophic factors that have nearly 50% amino acid sequence homology with each other. NGF is known to support survival and stimulate differentiation of sympathetic and neural crest-derived some sensory neurons in the peripheral nervous system and the basal forebrain cholinergic neurons in the central nervous system. Recent investigations have expanded NGF action to much wider cell populations than previously known. Namely, NGF stimulates differentiation and/or proliferation of immune cells including lymphocytes, leucocytes and mast cells. These findings suggest important roles of NGF in the crosstalk between the nervous system and immune system. Therefore, a practical and sensitive method to quantify physiological NGF is in great demand. We developed a sensitive twosite enzyme immunoassay (EIA) system for mouse NGF, based on the sandwiching of the antigen between anti-mouse NGF antibody IgG coated to a plastic plate and biotinylated-anti-NGF antibody. Avidin-β-D-galactosidase was then bound to biotines, and galactosidase activity was determined fluorometrically. This method is simple, rapid and sensitive. Purified NGF is detectable at a concentration as low as a few pg/ml, which is enough to detect physiological NGF in various tissues and NGF secreted from cultured non-neuronal cells such as fibroblasts, astrocytes and Schwann cells.