Constitutive and ghrelin-dependent GHSR1a activation impairs CaV2.1 and CaV2.2 currents in hypothalamic neurons.
Constitutive and ghrelin-dependent GHSR1a activation impairs CaV2.1 and CaV2.2 currents in hypothalamic neurons.
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DOI：
10.1085/jgp.201511383
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发表时间：
2015-09
期刊：
影响因子：
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通讯作者：
Raingo J
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文献类型：
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作者：
López Soto EJ;Agosti F;Cabral A;Mustafa ER;Damonte VM;Gandini MA;Rodríguez S;Castrogiovanni D;Felix R;Perelló M;Raingo J
组成型和配体依赖性GHSR1a活性通过不同的机制和信号通路减弱CaV2电流和下丘脑GABA释放。生长激素促分泌受体1a型（GHSR1a）是已知的G蛋白偶联受体（GPCR）中组成活性最高的。GHSR1a介导激素ghrelin的作用，其激活增加下丘脑神经元的转录和电活动。虽然GHSR1a存在于gaba能突触前末端，但其对神经递质释放的影响尚不清楚。介导突触前末端神经递质释放的电压门控钙通道CaV2.1和CaV2.2的活性受到多种gpcr的调节。本研究表明，在大鼠和小鼠下丘脑神经元和异源表达系统中，构成型和激动剂依赖性的GHSR1a活性都会引起CaV2.1和CaV2.2电流的强烈损伤。GHSR1a活性通过Gi/o依赖性机制减少CaV2电流，该机制涉及质膜通道密度的持续降低，而ghrelin依赖性GHSR1a抑制是可逆的，并通过gq依赖性途径改变CaV2门通。因此，GHSR1a通过Gi/o或Gq蛋白途径抑制CaV2通道的差异取决于其激活模式。此外，我们提供的证据表明，ghsr1a介导的CaV2抑制会减弱下丘脑神经元中GABA的释放，这一机制可能通过突触后神经元的去抑制来促进神经元的激活。
Constitutive and ligand-dependent GHSR1a activity attenuates CaV2 current and hypothalamic GABA release through distinct mechanisms and signaling pathways. The growth hormone secretagogue receptor type 1a (GHSR1a) has the highest known constitutive activity of any G protein–coupled receptor (GPCR). GHSR1a mediates the action of the hormone ghrelin, and its activation increases transcriptional and electrical activity in hypothalamic neurons. Although GHSR1a is present at GABAergic presynaptic terminals, its effect on neurotransmitter release remains unclear. The activities of the voltage-gated calcium channels, CaV2.1 and CaV2.2, which mediate neurotransmitter release at presynaptic terminals, are modulated by many GPCRs. Here, we show that both constitutive and agonist-dependent GHSR1a activity elicit a strong impairment of CaV2.1 and CaV2.2 currents in rat and mouse hypothalamic neurons and in a heterologous expression system. Constitutive GHSR1a activity reduces CaV2 currents by a Gi/o-dependent mechanism that involves persistent reduction in channel density at the plasma membrane, whereas ghrelin-dependent GHSR1a inhibition is reversible and involves altered CaV2 gating via a Gq-dependent pathway. Thus, GHSR1a differentially inhibits CaV2 channels by Gi/o or Gq protein pathways depending on its mode of activation. Moreover, we present evidence suggesting that GHSR1a-mediated inhibition of CaV2 attenuates GABA release in hypothalamic neurons, a mechanism that could contribute to neuronal activation through the disinhibition of postsynaptic neurons.