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

Non‐technical summary Normal 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. Normal 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. IKACh relaxation refers to a slow decrease or increase in current magnitude with depolarization or hyperpolarization, respectively. The molecular mechanism underlying this perplexing gating behaviour remains unclear. Here, we consider a novel explanation for IKACh relaxation based upon the recent finding that G‐protein‐coupled receptors (GPCRs) are intrinsically voltage sensitive and that the muscarinic agonists acetylcholine (ACh) and pilocarpine (Pilo) manifest opposite voltage‐dependent IKACh modulation. We show that Pilo activation of IKACh displays relaxation characteristics opposite to that of ACh. We explain the opposite effects of ACh and Pilo using Markov models of IKACh that incorporate ligand‐specific, voltage‐dependent parameters. Based on experimental and computational findings, we propose a novel molecular mechanism to describe the enigmatic relaxation gating process: IKACh relaxation represents a voltage‐dependent change in agonist affinity as a consequence of a voltage‐dependent conformational change in the muscarinic receptor.