In Silico Study on Short-Term Desensitization of Muscarinic K+ Current in the Heart

Abstract

Acetylcholine (ACh) increases the amplitude of cardiac K⁺ current (I_K.ACh) through activation of the muscarinic K⁺ (K_ACh) channel, but the amplitude gradually decreases to a quasi-steady-state level within seconds. This phenomenon, known as short-term desensitization, is believed to play a role in cellular adaptation to external input. However, the precise mechanism and physiological role of short-term desensitization is still unclear. In the present review, we introduced our experimental and theoretical studies on the mechanisms underlying short-term desensitization of I_K.ACh. In atrial myocytes, short-term desensitization features the unique dose responses of the transient and quasi-steady state I_K.ACh, effects of ACh preperfusion and recovery from short-term desensitization. In simulation analysis, two conditions are required for the mathematical I_K.ACh model to reconstitute short-term desensitization. The first condition is distinct muscarinic receptors (M₂Rs) with different affinities for ACh, which conferred an I_K.ACh response over a wide range of ACh concentrations. The second condition is 2 distinct K_ACh channels with different affinities for the G-proteinβγsubunit, which contributes to reconstitution of the temporal behavior of I_K.ACh. Under these conditions, the model quantitatively reproduced the unique properties of short-term desensitization observed in experiments. Furthermore, the present model conferred vagal escape on the mathematical action potential models of sinus node cells. Therefore, 2 different populations of K_ACh channels and M₂Rs may be responsible for short-term desensitization and vagal escape at nodal cells.