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Department of Pharmacology II, Graduate School of Medicine, Osaka University, 2-2 Yamada-oka, Suita, Osaka 565-0871, Japan
G protein-gated inward rectifier K+ (KG) channels are directly activated by the ß
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 KG channels are critically determined by mechanisms which regulate their activity and their subcellular localization. KG channels are tetramers of inward rectifier K+ (Kir) channel subunits, Kir3.x. The combination of Kir3.x subunits in each KG channel varies among tissues and cell types. Each subunit of the channel possesses one Gß binding site. The binding of Gß increases the number of functional KG channels via a mechanism that can be described by the Monod–Wyman–Changeux allosteric model. During voltage pulses KG channel current alters time dependently. The KG current exhibits inward rectification due to blockade of outward-going current by intracellular Mg2+ 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 G
subunit. Thus, the relaxation behaviour of KG channels reflects the time course with which the G protein cycle is altered by RGS protein activity at each membrane potential. Subcellular localization of KG channels is controlled by several distinct mechanisms, some of which have been recently clarified. The neuronal KG 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 KG 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, KG 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.
(Received 3 June 2003;
accepted after revision 12 August 2003;
first published online 15 August 2003)
Corresponding author Y. Kurachi: Department of Pharmacology II, Graduate School of Medicine, Osaka University, 2-2 Yamada-oka, Suita, Osaka 565-0871, Japan. Email: ykurachi{at}pharma2.med.osaka-u.ac.jp
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