Receptor-induced depletion of phosphatidylinositol 4,5-bisphosphate inhibits inwardly rectifying K+ channels in a receptor-specific manner.

Abstract:

:Phosphatidylionsitol 4,5-bisphosphate (PIP(2)), a substrate of phospholipase C, has recently been recognized to regulate membrane-associated proteins and act as a signal molecule in phospholipase C-linked Gq-coupled receptor (GqPCR) pathways. However, it is not known whether PIP(2) depletion induced by GqPCRs can act as receptor-specific signals in native cells. We investigated this issue in cardiomyocytes where PIP(2)-dependent ion channels, G protein-gated inwardly rectifying K(+) (GIRK) and inwardly rectifying background K(+) (IRK) channels, and various GqPCRs are present. The GIRK current was recorded by using the patch-clamp technique during the application of 10 microM acetylcholine. The extent of receptor-mediated inhibition was estimated as the current decrease over 4 min while taking the GIRK current (I(GIRK)) value during a previous stimulation as the control. Each GqPCR agonist inhibited I(GIRK) with different potencies and kinetics. The extents of inhibition induced by phenylephrine, angiotensin II, endothelin-1, prostaglandin F2alpha, and bradykinin at supramaximal concentrations were (mean +/- SE) 32.1 +/- 0.6%, 21.9 +/- 1.4%, 86.4 +/- 1.6%, 63.7 +/- 4.9%, and 5.7 +/- 1.9%, respectively. GqPCR-induced inhibitions of I(GIRK) were not affected by protein kinase C inhibitor (calphostin C) but potentiated and became irreversible when the replenishment of PIP(2) was blocked by wortmannin (phosphatidylinositol kinase inhibitor). Loading the cells with PIP(2) significantly reduced endothelin-1 and prostaglandin F2alpha-induced inhibition of I(GIRK). On the contrary, GqPCR-mediated inhibitions of inwardly rectifying background K(+) currents were observed only when GqPCR agonists were applied with wortmannin, and the effects were not parallel with those on I(GIRK). These results indicate that GqPCR-induced inhibition of ion channels by means of PIP(2) depletion occurs in a receptor-specific manner.

authors

Cho H,Lee D,Lee SH,Ho WK

doi

10.1073/pnas.0408844102

keywords:

subject

Has Abstract

pub_date

2005-03-22 00:00:00

pages

4643-8

issue

12

eissn

0027-8424

issn

1091-6490

pii

0408844102

journal_volume

102

pub_type

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