Relaxation gating of the acetylcholine-activated inward rectifier K+ current is mediated by intrinsic voltage sensitivity of the muscarinic receptor

摘要

Non-technical summaryNormal heart rate variability is critically dependent upon the G-protein-coupled, acetylcholine (ACh)-activated inward rectifier K⁺ current, IKACh. A unique feature of IKACh is the so-called ‘relaxation’ gating property that contributes to increased current at hyperpolarized membrane potentials. Here, we consider a novel explanation for IKACh relaxation based upon the recent finding that G-protein-coupled receptors are intrinsically voltage sensitive and that the muscarinic agonists acetylcholine and pilocarpine manifest opposite voltage-dependent IKACh modulation. Based on experimental and computational findings, we propose that IKACh relaxation represents a voltage-dependent change in agonist affinity as a consequence of a voltage-dependent conformational change in the muscarinic receptor.