Differential regulation of synaptic and extrasynaptic α4 GABA(A) receptor populations by protein kinase A and protein kinase C in cultured cortical neurons.
Differential regulation of synaptic and extrasynaptic α4 GABA(A) receptor populations by protein kinase A and protein kinase C in cultured cortical neurons.
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DOI：
10.1016/j.neuropharm.2016.01.009
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发表时间：
2016-06
影响因子：
4.7
通讯作者：
Morrow AL
中科院分区：
文献类型：
--
作者：
Bohnsack JP;Carlson SL;Morrow AL
GABAA α4亚基存在于两个不同的GABAA受体群体中。突触GABAA α4受体位于突触处并介导相位抑制性神经传递，而突触外GABAA受体位于突触外并介导紧张性抑制性传递。这些受体具有独特的药理学和生物物理学特性，有助于人们对这些不同亚型在生理和病理状态下如何调节感兴趣。我们利用亚细胞分离程序来分离这些受体群体，以研究它们在皮层培养神经元中的蛋白激酶调节。蛋白激酶A（PKA）激活降低突触α4表达，而蛋白激酶C（PKC）激活增加α4亚基表达，这些作用分别与β3 S408/409或γ2 S327磷酸化增加有关。相反，PKA激活增加突触外α4和δ亚基表达，而PKC激活没有影响。我们的研究结果表明，突触和突触外GABAA α4亚单位的表达可以通过PKA调节，为涉及GABA能传递缺陷的神经系统疾病提供更具体的治疗方法。
The GABAA α4 subunit exists in two distinct populations of GABAA receptors. Synaptic GABAA α4 receptors are localized at the synapse and mediate phasic inhibitory neurotransmission, while extrasynaptic GABAA receptors are located outside of the synapse and mediate tonic inhibitory transmission. These receptors have distinct pharmacological and biophysical properties that contribute to interest in how these different subtypes are regulated under physiological and pathological states. We utilized subcellular fractionation procedures to separate these populations of receptors in order to investigate their regulation by protein kinases in cortical cultured neurons. Protein kinase A (PKA) activation decreases synaptic α4 expression while protein kinase C (PKC) activation increases α4 subunit expression, and these effects are associated with increased β3 S408/409 or γ2 S327 phosphorylation respectively. In contrast, PKA activation increases extrasynaptic α4 and δ subunit expression, while PKC activation has no effect. Our findings suggest synaptic and extrasynaptic GABAA α4 subunit expression can be modulated by PKA to inform the development of more specific therapeutics for neurological diseases that involve deficits in GABAergic transmission.