Neuroscience
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The neurosteroid allopregnanolone (ALLO) or 3alpha-OH-5alpha-pregnane-20-one interacts with the GABA type A receptor chloride ion channel complex and enhances the effect of GABA. Animal and human studies suggest that ALLO plays an important role in several disorders including premenstrual syndrome, anxiety, and memory impairment. In contrast to ALLO, steroids with a hydroxy group in the 3beta position usually exert a reducing effect and have recently attracted interest due to their suggested role in counteracting the negative action of ALLO. ⋯ However, in the absence of ALLO, two of the 3beta-steroids potentiated GABA-evoked chloride ion uptake and prolonged the sIPSCs decay time, whereas the others had little or no effect. Therefore, it is possible that at least some 3beta-steroids can act as positive GABA(A) receptor modulators as well as negative modulators depending on whether or not ALLO is present. Finally, these results suggest that the 3beta-steroids could be of interest as pharmacological agents that could counteract the negative effects of ALLO.
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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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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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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.