Larger transient outward K+ current and shorter action potential duration in Gα11 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.

Long-term treatment of spontaneously hypertensive rats with losartan and molecular basis of modulating Ito of ventricular myocytes

“…Thus, the present study suggests that systemic hypertension may decrease I to density by reducing the expression of Kv4.2 and Kv4.3 transcripts and by increasing the expression of KChIP2 transcripts. The results are consistent with those of a previous study (14).…”

How Gastrin-Releasing Peptide Opens the Spinal Gate for Itch

“…The 7 mV-depolarization of the RMP reduced the amplitude of A-type potassium currents by 61.9% ± 5.3% (n = 11, p < 0.0001, two-sided paired t test) (Figure 6D). Because A-type potassium channels are not only inactivated by prolonged depolarization but also inhibited by phosphorylation via extracellular signal-regulated kinase (Erk) (Hu et al., 2003), which can be initiated by Gα q/11 -dependent signaling (Wagner et al., 2010), we tested whether the A-type potassium currents in GRPR neurons are also directly modulated by GRP. Under voltage-clamp conditions, A-type potassium currents were not changed by GRP (300 nM) (Figure 6E).…”

“…Their pharmacological inhibition with 4-aminopyridine (Ruscheweyh and Sandkühler, 2002, Yoshimura and Jessell, 1989) or genetic ablation of the underlying Kv4.2 channels (Hu et al., 2006) increase the excitability of dorsal horn neurons. A-type potassium channels, in particular, Kv4.2 channels, are not only inactivated by prolonged depolarization but also by phosphorylation via Gα q/11 -dependent extracellular signal regulated kinase (Erk) (Hu et al., 2003, Wagner et al., 2010). Furthermore, it has been suggested that GRPR-mediated itch responses occur through downstream activation of the phosphoinositid 3-kinase γ (PI3Kγ)/Akt pathway (Pereira et al., 2015).…”

An Investigation of the Altered Textural Property in Woody Breast Myopathy Using an Integrative Omics Approach

“…This chain reaction signals SR to release calcium resulting in elevating the sarcoplasmic calcium level ( Alvarez-Curto et al, 2016 ). Wagner et al (2010) found that knockout G protein G11 alpha-subunit and G protein q polypeptide mice had shorter action potential compared to the wild type. Therefore, the observed upregulation of G protein-coupled acetylcholine receptor signaling pathway could translate into prolonged action potential leading to potentially more calcium release from the SR. On the other hand, synaptophysin-like protein 2 (SYPL2), was found to be downregulated in WB compared to the N samples ( p < 0.05).…”