title: Regulatory mechanisms underlying the modulation of GIRK1/GIRK4 heteromeric channels by P2Y receptors.
abstract: The muscarinic K(+) channel (I                         (K,ACh)) is a heterotetramer composed of GIRK1 (Kir3.1) and GIRK4 (Kir3.4) subunits of a G protein-coupled inwardly rectifying channel, and plays an important role in mediating electrical responses to the vagal stimulation in the heart. I                         (K,ACh) displays biphasic changes (activation followed by inhibition) through the stimulation of the purinergic P2Y receptors, but the regulatory mechanism involved in these modulation of I                         (K,ACh) by P2Y receptors remains to be fully elucidated. Various P2Y receptor subtypes and GIRK1/GIRK4 (I                         (GIRK)) were co-expressed in Chinese hamster ovary cells, and the effect of stimulation of P2Y receptor subtypes on I                         (GIRK) were examined using the whole-cell patch-clamp method. Extracellular application of 10 μM ATP induced a transient activation of I                         (GIRK) through the P2Y(1) receptor, which was completely abolished by pretreatment with pertussis toxin. ATP initially caused an additive transient increase in ACh-activated I                         (GIRK) (via M(2) receptor), which was followed by subsequent inhibition. This inhibition of I                         (GIRK) by ATP was attenuated by co-expression of regulator of G-protein signaling 2, or phosphatidylinositol-4-phosphate-5-kinase, or intracellular phosphatidylinositol 4,5-bisphosphate loading, but not by the exposure to protein kinase C inhibitors. P2Y(4) stimulation also persistently suppressed the ACh-activated I                         (GIRK). In addition, I                         (GIRK) evoked by the stimulation of the P2Y(4) receptor exhibited a transient activation, but that evoked by the stimulation of P2Y(2) or P2Y(12) receptor showed a rather persistent activation. These results reveal (1) that P2Y(1) and P2Y(4) are primarily coupled to the G(q)-phospholipase C-pathway, while being weakly linked to G(i/o), and (2) that P2Y(2) and P2Y(12) involve G(i/o) activation.
authors.affiliation: Department of Pharmacology, Medical School of Xi'an Jiaotong University, Xi'an, Shaanxi, People's Republic of China.
authors.forename: Jie
authors.initials: J
authors.lastname: Wu
authors.forename: Wei-Guang
authors.initials: WG
authors.lastname: Ding
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Matsuura
authors.forename: Minoru
authors.initials: M
authors.lastname: Horie
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels / Q000378:metabolism*; D019204:GTP-Binding Proteins / Q000378:metabolism; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D018408:Patch-Clamp Techniques; D058472:Receptors, Purinergic P2Y1 / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology
chemical_list: D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels; D058472:Receptors, Purinergic P2Y1; D000255:Adenosine Triphosphate; D019204:GTP-Binding Proteins