Kurachi Yoshihisa, Ishii Masaru
Department of Pharmacology II, Graduate School of Medicine, Osaka University, 2-2 Yamada-oka, Suita, Osaka 565-0871, Japan.
J Physiol. 2004 Jan 15;554(Pt 2):285-94. doi: 10.1113/jphysiol.2003.048439. Epub 2003 Aug 15.
G protein-gated inward rectifier K(+) (K(G)) channels are directly activated by the betagamma subunits released from pertussis toxin-sensitive G proteins, and contribute to neurotransmitter-induced deceleration of heart beat, formation of slow inhibitory postsynaptic potentials in neurones and inhibition of hormone release in endocrine cells. The physiological roles of K(G) channels are critically determined by mechanisms which regulate their activity and their subcellular localization. K(G) channels are tetramers of inward rectifier K(+) (Kir) channel subunits, Kir3.x. The combination of Kir3.x subunits in each K(G) channel varies among tissues and cell types. Each subunit of the channel possesses one Gbetagamma binding site. The binding of Gbetagamma increases the number of functional K(G) channels via a mechanism that can be described by the Monod-Wyman-Changeux allosteric model. During voltage pulses K(G) channel current alters time dependently. The K(G) current exhibits inward rectification due to blockade of outward-going current by intracellular Mg(2+) and polyamines. Upon repolarization, this blockade is relieved practically instantaneously and then the current slowly increases further. This slow current alteration is called 'relaxation'. Relaxation is caused by the voltage-dependent behaviour of regulators of G protein signalling (RGS proteins), which accelerate intrinsic GTP hydrolysis mediated by the Galpha subunit. Thus, the relaxation behaviour of K(G) channels reflects the time course with which the G protein cycle is altered by RGS protein activity at each membrane potential. Subcellular localization of K(G) channels is controlled by several distinct mechanisms, some of which have been recently clarified. The neuronal K(G) channel, which contains Kir3.2c, is localized in the postsynaptic density (PSD) of various neurones including dopaminergic neurones in substantia nigra. Its localization at PSD may be controlled by PDZ domain-containing anchoring proteins. The K(G) channel in thyrotrophs is localized exclusively on secretary vesicles, which upon stimulation are rapidly inserted into the plasma membrane and causes hyperpolarization of the cell. This mechanism indicates a novel negative feedback regulation of exocytosis. In conclusion, K(G) channels are under the control of a variety of signalling molecules which regulate channel activity, subcellular localization and thus their physiological roles in myocytes, neurones and endocrine cells.
G蛋白门控内向整流钾（K(G)）通道直接由百日咳毒素敏感的G蛋白释放的βγ亚基激活，有助于神经递质诱导的心跳减速、神经元中缓慢抑制性突触后电位的形成以及内分泌细胞中激素释放的抑制。K(G)通道的生理作用关键取决于调节其活性和亚细胞定位的机制。K(G)通道是内向整流钾（Kir）通道亚基Kir3.x的四聚体。每个K(G)通道中Kir3.x亚基的组合在不同组织和细胞类型中有所不同。通道的每个亚基都有一个Gβγ结合位点。Gβγ的结合通过一种可以用莫诺德-怀曼-尚热变构模型描述的机制增加功能性K(G)通道的数量。在电压脉冲期间，K(G)通道电流随时间变化。由于细胞内Mg(2+)和多胺对外向电流的阻断，K(G)电流表现出内向整流。复极化时，这种阻断几乎瞬间解除，然后电流进一步缓慢增加。这种缓慢的电流变化称为“松弛”。松弛是由G蛋白信号调节因子（RGS蛋白）的电压依赖性行为引起的，RGS蛋白加速由Gα亚基介导的内在GTP水解。因此，K(G)通道的松弛行为反映了在每个膜电位下RGS蛋白活性改变G蛋白循环的时间进程。K(G)通道的亚细胞定位由几种不同的机制控制，其中一些最近已经阐明。含有Kir3.2c的神经元K(G)通道定位于包括黑质多巴胺能神经元在内的各种神经元的突触后密度（PSD）中。其在PSD的定位可能由含PDZ结构域的锚定蛋白控制。促甲状腺细胞中的K(G)通道仅定位于分泌囊泡上，受到刺激时，这些囊泡会迅速插入质膜并导致细胞超极化。这种机制表明了一种新的胞吐作用负反馈调节。总之，K(G)通道受多种信号分子的控制，这些信号分子调节通道活性、亚细胞定位，从而调节其在心肌细胞、神经元和内分泌细胞中的生理作用。
