Altered cardiac chronotropic responses in βARK 2 knockout mice
G protein-coupled receptor kinases (GRKs) desensitize agonist-activated G protein-coupled receptors (GPCRs) thus attenuating their responses. In cell culture experiments, GRK 3 (βARK 2) phosphorylates and desensitizes multiple GPCRs, including muscarinic acetylcholine receptors (mAChR). Genetically altered mice, lacking βARK 2 (βARK 2 -/-), display a more rapid heart rate recovery after an i.v. injection of methacholine, than wildtype mice (WT). Since this observation is contrary to that expected (assuming βARK 2 desensitizes cardiac m2AChR in vivo) and given that i.v. methacholine induces hypotension, we hypothesized that BARK 2 may desensitize a central component of cardiovascular control, the baroreceptor reflex. To test this hypothesis we examined baroreflexes as well as the impact of direct cardiac m2AChR activation with vagal stimulation. During vagal nerve stimulation (10, 15 and 20 Hz) heart rate decreased, and recovered, similarly in βARK 2 -/- and WT mice. However, the increase in heart rate associated with sodium nitroprusside-induced hypotension was significantly greater in βARK 2 -/- (88 ± 12 beats/min) than WT (31 ± 16 beats/min) mice. Interestingly, propranolol significantly decreased resting heart rate in WT (486 ± 28 to 419 ± 22 beats/min), but not βARK 2 -/-mice (443 ±26 to 426 ± 25 beats/min). In conclusion, the cardiac component of the baroreceptor reflex is likely responsible for the chronotropic differences observed between βARK 2 -/- and WT mice.
Walker, JKL; Peppel, K; Lefkowitz, RJ; Caron, MG; Fisher, JT
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