Melanocortins and agouti-related protein modulate the excitability of two arcuate nucleus neuron populations by alteration of resting potassium conductances
Melanocortins and agouti-related protein modulate the excitability of two arcuate nucleus neuron populations by alteration of resting potassium conductances
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DOI：
10.1113/jphysiol.2006.119479
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发表时间：
2007-01-15
影响因子：
5.5
通讯作者：
Ashford, Michael L. J.
中科院分区：
文献类型：
--
作者：
Smith, Mark A.;Hisadome, Kazunari;Ashford, Michael L. J.
下丘脑黑皮质素系统对于控制食欲和体重至关重要。五种黑皮质素受体中的两种，MC3R和MC4R参与下丘脑对能量稳态的控制，其中MC4R具有主要影响。通常认为黑皮质素系统对下丘脑回路的主要影响在弓状核外部，并且弓状核中的任何局部作用对阿黑皮素原表达（POMC）神经元具有抑制作用。相比之下，使用电流和电压钳记录从确定的神经元，我们表明，MC3R和MC4R激动剂decompensate弓状POMC神经元和一个单独的弓状神经元群体确定的大鼠胰岛素2启动子（RIPCre）转基因表达。此外，内源性MC3R和MC4R拮抗剂，刺鼠相关蛋白（AgRP），超极化POMC和RIPCre神经元的黑皮质素激动剂的情况下，在MC4R的反向激动一致。瞬时外向（I（A））钾电导的降低，以及较小程度的内向整流（K（IR））电导，是神经元去极化的基础，而I（A）的增加介导AgRP诱导的超极化。因此，POMC和RIPCre神经元可能是肽递质的靶点，这些肽递质可能从弓状核中表达AgRP的神经元和POMC神经元局部释放，进一步增加了弓状系统先前未被认识到的复杂性。
The hypothalamic melanocortin system is crucial for the control of appetite and body weight. Two of the five melanocortin receptors, MC3R and MC4R are involved in hypothalamic control of energy homeostasis, with the MC4R having the major influence. It is generally thought that the main impact of the melanocortin system on hypothalamic circuits is external to the arcuate nucleus, and that any effect locally in the arcuate nucleus is inhibitory on proopiomelanocortin-expressing (POMC) neurons. In contrast, using current- and voltage-clamp recordings from identified neurons, we demonstrate that MC3R and MC4R agonists depolarize arcuate POMC neurons and a separate arcuate neuronal population identified by the rat insulin 2 promoter (RIPCre) transgene expression. Furthermore, the endogenous MC3R and MC4R antagonist, agouti-related protein (AgRP), hyperpolarizes POMC and RIPCre neurons in the absence of melanocortin agonist, consistent with inverse agonism at the MC4R. A decreased transient outward (I(A)) potassium conductance, and to a lesser extent the inward rectifier (K(IR)) conductance, underlies neuronal depolarization, whereas an increase in I(A) mediates AgRP-induced hyperpolarization. Accordingly, POMC and RIPCre neurons may be targets for peptide transmitters that are possibly released locally from AgRP-expressing and POMC neurons in the arcuate nucleus, adding further previously unappreciated complexity to the arcuate system.