In-silico assessment of the influence of the membrane voltage and agonist/antagonist binding dependent M2 muscarinic receptor on IKACh in the rabbit sinus node and atrium
The normal heart rate is mediated by 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. The Diploma thesis is considering a novel explanation for IKACh relaxation based upon 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, Moreno-Galindo et al. proposed that IKACh relaxation represents a voltage-dependent change in agonist affinity as a consequence of a voltage-dependent conformational change in the muscarinic receptor.
During this work, a new model of the muscarinic receptor, IKACh and their interaction should be developed based on a Markov approach. The parameters of the model than should be adjusted to rabbit measurement data and integrated into models of rabbit cell electrophysiology of the sinus node and the atrium. The effects of changing membrane voltage under varying concentration of acetylcholine and pilocarpine should be investigated.