Neuroscience
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A subgroup of dorsal root ganglion (DRG) neurons responds to noxious heat with an influx of cations carried by specific ion channels such as the transient receptor potential channel of the vanilloid receptor type, subtype 1 (TRPV1). Application of capsaicin induces a reversible facilitation of these currents. This facilitation could be an interaction of two agonists at their common receptor or be caused by an influx of calcium ions into the cell. ⋯ Application of the MEK inhibitor U0126 also inhibited facilitation of Iheat by capsaicin. We conclude that the MEK/ERK cascade is an intracellular signaling pathway playing a vital role in the regulation of nociceptive neurons' sensitivity. The very fast kinetics (less than two seconds) are only explainable with a membrane-attached or at least membrane-near localization of these kinases.
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Overexpression of alpha-synuclein causes familial Parkinson's disease and abnormal aggregates of the protein are present in sporadic cases of the disease. We have examined the behavioral effects of direct and indirect dopaminergic agonists in transgenic mice expressing human alpha-synuclein under the Thy-1 promoter (Thy1-aSyn, alpha-synuclein overexpressor), which exhibit progressive impairments in behavioral tests sensitive to nigrostriatal dopamine dysfunction. ⋯ In contrast to wild-type mice, Thy1-aSyn mice did not show amphetamine-induced stereotypies. The results indicate that chronic overexpression of alpha-synuclein led to abnormal pharmacological responses in mice.
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The ionotropic GABA(C) receptor, formed by GABA rho subunits, is known to be modulated by a variety of endogenous compounds, as well as by changes in pH. In this study, we explore the proton sensitivity of the GABA rho subunits cloned from the perch retina, and report a novel action of high pH on the homomeric receptor formed by one of the GABA rho subunits, the perch-rho(1B) subunit. Raising extracellular pH to 9.5 significantly accelerated GABA deactivation responses elicited from oocytes expressing the perch-rho(1B) subunit, and reduced its sensitivity to GABA. ⋯ When considered in terms of a model describing the activation of GABA(C) receptors, in which pH can potentially affect either the binding affinity or the rate of channel closure, the results were consistent with the view that external alkalization reduces the gating efficiency of the receptor. To identify the proton sensitive domain(s) of the perch-rho(1B) receptor, chimeras were constructed by domain swapping with other perch-rho subunits. Analysis of the pH sensitivities of the various chimeric receptors revealed that the alkaline-sensitive residues are located in the N-terminal region of the perch-rho(1B) subunit.
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Hereditary creatine transporter deficiency causes brain damage, despite the brain having the enzymes to synthesize creatine. Such damage occurring despite an endogenous synthesis is not easily explained. This condition is incurable, because creatine may not be delivered to the brain without its transporter. ⋯ Since there is a strong indication that creatine in the brain is mainly synthesized by glial cells and transferred to neurons, this might explain why hereditary transporter deficiency is attended by severe brain damage despite the possibility of an endogenous synthesis. CrOBzl and PCr-Mg-CPLX cross the plasma membrane in a transporter-independent way, and might be useful in the therapy of hereditary creatine transporter deficiency. They may also prove useful in the therapy of brain anoxia or ischemia.
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Neuronal gap junctions are abundant in both outer and inner plexiform layers of the mammalian retina. In the inner plexiform layer (IPL), ultrastructurally-identified gap junctions were reported primarily in the functionally-defined and anatomically-distinct ON sublamina, with few reported in the OFF sublamina. We used freeze-fracture replica immunogold labeling and confocal microscopy to quantitatively analyze the morphologies and distributions of neuronal gap junctions in the IPL of adult rat and mouse retina. ⋯ Under these conditions, string and ribbon gap junctions remained abundant in the OFF sublamina and absent in the ON sublamina. Abundant gap junctions in the OFF sublamina of these two rodents with rod-dominant retinas revealed previously-undescribed but extensive pathways for inter-neuronal communication; and the wide dispersion of connexons in string and ribbon gap junctions suggests unique structural features of gap junctional coupling in the OFF vs. ON sublamina.