title: Larger transient outward K(+) current and shorter action potential duration in Galpha(11) mutant mice.
abstract: The alpha(1)-adrenoceptor as well as the AT(1)- and the ET(A)-receptor couple to G-proteins of the Galpha(q/11) family and contribute to the regulation of the transient outward K(+) current (I(to,f)) under pathological conditions such as cardiac hypertrophy or failure. This suggests an important role of Galpha(q/11)-signalling in the physiological regulation of I(to,f). Here, we investigate mice deficient of the Galpha(11) protein (gna11(-/-)) to clarify the physiological role of Galpha(11) signalling in cardiac ion channel regulation. Myocytes from endocardial and epicardial layers were isolated from the left ventricular free wall and investigated using the ruptured-patch whole-cell patch-clamp technique. At +40 mV, epicardial myocytes from gna11(-/-) mice displayed a 23% larger I(to,f) than controls (52.6 + or - 4.1 pApF(-1), n = 20 vs 42.7 + or - 2.8 pApF(-1), n = 26, p < 0.05). Endocardial I(to,f) was similar in gna11(-/-) mice and controls. With the except of minor changes in endocardial myocytes, I(to,f) kinetics were similar in both groups. In the epicardial layer, western blot analysis revealed a 19% higher expression of the K(+)-channel alpha-subunit Kv4.2 in gna11(-/-) mice than in wild type (wt; p < 0.05). The beta-subunit KChIP2b was upregulated by 102% in epicardial myocytes of gna11(-/-) mice (p < 0.01, n = 4). Consistent with the difference in I(to,f), action potential duration was shorter in epicardial cells of gna11(-/-) mice than in wt (p < 0.05), while no difference was found in endocardial myocytes. These results suggest that Galpha(11)-coupled signalling is a central pathway in the regulation of I(to,f). It physiologically exerts a tonic inhibitory influence on the expression of I(to,f) and thereby contributes to the regulation of cardiac repolarisation.
authors: Institut für Zelluläre und Molekulare Physiologie, Friedrich-Alexander-Universität Erlangen-Nürnberg, Waldstrasse 6, 91054, Erlangen, Germany.
authors: Michael
authors: M
authors: Wagner
authors: Elena
authors: E
authors: Rudakova
authors: Vera
authors: V
authors: Schütz
authors: Magdalena
authors: M
authors: Frank
authors: Heimo
authors: H
authors: Ehmke
authors: Tilmann
authors: T
authors: Volk
mesh_terms: D000200:Action Potentials / Q000502:physiology*; D000818:Animals; D043802:GTP-Binding Protein alpha Subunits, Gq-G11 / Q000235:genetics / Q000378:metabolism; D006801:Humans; D015640:Ion Channel Gating; D051605:Kv Channel-Interacting Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D032383:Myocytes, Cardiac / Q000166:cytology / Q000378:metabolism; D018408:Patch-Clamp Techniques; D011188:Potassium / Q000378:metabolism*; D051672:Shal Potassium Channels / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology
chemical_list: C496755:Kcnip2 protein, mouse; D051605:Kv Channel-Interacting Proteins; D051672:Shal Potassium Channels; D043802:GTP-Binding Protein alpha Subunits, Gq-G11; D011188:Potassium