Convergent phosphomodulation of the major neuronal dendritic potassium channel Kv4.2 by pituitary adenylate cyclase-activating polypeptide.
Convergent phosphomodulation of the major neuronal dendritic potassium channel Kv4.2 by pituitary adenylate cyclase-activating polypeptide.
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DOI：
10.1016/j.neuropharm.2015.10.006
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发表时间：
2016-02
影响因子：
4.7
通讯作者：
Mohapatra DP
中科院分区：
文献类型：
--
作者：
Gupte RP;Kadunganattil S;Shepherd AJ;Merrill R;Planer W;Bruchas MR;Strack S;Mohapatra DP
内源性神经肽垂体腺苷环化酶激活多肽(PACAP)由脑和脊髓中的神经细胞和非神经细胞分泌，对中风、癫痫、慢性炎症和神经病理性疼痛等病理条件做出反应。PACAP具有多种神经调节和神经保护作用。然而，PACAP对固有的可兴奋离子通道的功能的直接影响仍然很大程度上仍未被探索。主要的树突状K+通道Kv4.2是神经元兴奋性、树突内反向传播动作电位和突触输入调制的关键调节因子。我们鉴定、克隆和鉴定了在啮齿动物海马神经元中表达的三种PACAP受体(PAC1)亚型的激活所产生的下游信号，这些亚型也表现出丰富的Kv4.2蛋白表达。PACAP激活PAC1导致Kv4.2的磷酸化和通道电流的下调，这种作用可以通过抑制PKA或ERK1/2的活性来减弱。从机制上讲，Kv4.2功能的这种动态下调是表面通道密度降低的结果，而对通道激活的电压依赖性没有任何影响。有趣的是，PKA对Kv4.2的诱导作用是通过ERK1/2在两个关键残基上的磷酸化来实现的，而不是通过PKA直接的通道磷酸化来实现的，这意味着一个趋同的磷酸化信号级联。总之，我们的发现提示在PACAP/PAC1和Kv4.2通道之间存在一种新的GPCR通道信号串扰，这种信号串扰可能导致神经元的超兴奋性。
The endogenous neuropeptide pituitary adenylate cyclase-activating polypeptide (PACAP) is secreted by both neuronal and non-neuronal cells in the brain and spinal cord, in response to pathological conditions such as stroke, seizures, chronic inflammatory and neuropathic pain. PACAP has been shown to exert various neuromodulatory and neuroprotective effects. However, direct influence of PACAP on the function of intrinsically excitable ion channels that are critical to both hyperexcitation as well as cell death, remain largely unexplored. The major dendritic K+ channel Kv4.2 is a critical regulator of neuronal excitability, back-propagating action potentials in the dendrites, and modulation of synaptic inputs. We identified, cloned and characterized the downstream signaling originating from the activation of three PACAP receptor (PAC1) isoforms that are expressed in rodent hippocampal neurons that also exhibit abundant expression of Kv4.2 protein. Activation of PAC1 by PACAP leads to phosphorylation of Kv4.2 and downregulation of channel currents, which can be attenuated by inhibition of either PKA or ERK1/2 activity. Mechanistically, this dynamic downregulation of Kv4.2 function is a consequence of reduction in the density of surface channels, without any influence on the voltage-dependence of channel activation. Interestingly, PKA-induced effects on Kv4.2 were mediated by ERK1/2 phosphorylation of the channel at two critical residues, but not by direct channel phosphorylation by PKA, suggesting a convergent phosphomodulatory signaling cascade. Altogether, our findings suggest a novel GPCR-channel signaling crosstalk between PACAP/PAC1 and Kv4.2 channel in a manner that could lead to neuronal hyperexcitability.