Abstract:

The heart rate is mediated by the G protein-coupled muscarinic receptor (M2R) activating the acetylcholine (ACh)-dependent K+ current (IKACh). Here, a novel model for IKACh gating is presented based on recent findings that M2R agonist binding is voltage-sensitive. Furthermore, ACh and pilocarpine (Pilo) manifest opposite voltage-dependent IKACh modulation. In a previous work, a 4-state Markov model of M2R reconstructing the voltage-dependent change in agonist affinity was proposed. In this work, a 2-state Markov model of IKACh gating purely dependent on the Gβγ concentration is proposed. IKACh is modeled based on the description of Zhang et al. Measurement data are used to parametrize the combined M2R and IKACh model for both ACh and Pilo. The channel model has a linear Gβγ dependent forward and a constant backward rate. For ACh and Pilo, optimal values of model parameters are found reconstructing the measured opposite voltage-dependent change in agonist affinity. The combined model is able to reconstruct the measured data regarding the agonist and voltage-dependent properties of the M2R-IKACh channel complex. In future studies, this channel will be integrated in a sinus node model to investigate the effect of the channel properties on heart rate

Abstract:

The normal heart rate is mediated by the G-protein-coupled, acetylcholine (ACh)- activated inward rectifier K+ current (IK,ACh). A unique feature of IK,ACh is the so- called relaxation gating property that contributes to increased current at hyperpolarized membrane potentials. This Bachelor thesis is considering a novel explanation for IK,ACh relaxation based upon recent findings that G-protein-coupled receptors are intrinsically voltage sensitive and that the muscarinic agonists acetylcholine and pilocarpine manifest opposite voltage-dependent IK,ACh modulation. Based on experimental and computa- tional findings, [Moreno-Galindo et al., 2011] proposed that IK,ACh relaxation represents a voltage-dependent change in agonist affinity as a consequence of a voltage-dependent conformational change in the muscarinic receptor.