In:
Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 94, No. 15 ( 1997-07-22), p. 7921-7926
Abstract:
Cardiac muscarinic receptors activate an inwardly rectifying K + channel, I K + Ach , via pertussis toxin (PT)-sensitive heterotrimeric G proteins (in heart G i2 , G i3 , or G o ). We have used embryonic stem cell (ES cell)-derived cardiocytes with targeted inactivations of specific PT-sensitive α subunits to determine which G proteins are required for receptor-mediated regulation of I K + Ach in intact cells. The muscarinic agonist carbachol increased I K + Ach activity in ES cell-derived cardiocytes from wild-type cells, in cells lacking α o , and in cells lacking the PT-insensitive G protein α q . In cells with targeted inactivation of α i2 or α i3 , channel activation by both carbachol and adenosine was blocked. Carbachol-induced channel activation was restored in the α i2 - and α i3 -null cells by reexpressing the previously targeted gene and guanosine 5′-[γ-thio] triphosphate was able to fully activate I K + Ach in excised membranes patches from these mutants. In contrast, negative chronotropic responses to both carbachol and adenosine were preserved in cells lacking α i2 or α i3 . Our results show that expression of two specific PT-sensitive α subunits (α i2 and α i3 but not α o ) is required for normal agonist-dependent activation of I K + Ach and suggest that both α i2 - and α i3 -containing heterotrimeric G proteins may be involved in the signaling process. Also the generation of negative chronotropic responses to muscarinic or adenosine receptor agonists do not require activation of I K + Ach or the expression of α i2 or α i3 .
Type of Medium:
Online Resource
ISSN:
0027-8424
,
1091-6490
DOI:
10.1073/pnas.94.15.7921
Language:
English
Publisher:
Proceedings of the National Academy of Sciences
Publication Date:
1997
detail.hit.zdb_id:
209104-5
detail.hit.zdb_id:
1461794-8
SSG:
11
SSG:
12
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