Modeling VAS Deferens Smooth Muscle Electrophysiology: Role of Ion Channels in Generating Electrical Activity

Abstract

Premature ejaculation, which is a male sexual disorder is associated with abnormal spontaneous contraction of the vas deferens smooth muscle (VDSM). The VDSM cellular electrical activity, particularly the VDSM action potential (AP) performs an essential part in commencing VDSM contraction by allowing extracellular Ca2+ via the voltage-dependent Ca2+ channels. To explore the quantitative contribution of individual active ionic current to the AP generation, a biophysically detailed single VDSM cell model is presented. The ion channels' kinetics were characterized in terms of maximal conductances and differential equations based on voltage or calcium-dependent activation and inactivation. Then, all ion channels were integrated to generate the VDSM AP after introducing both current and neurotransmitter stimulus to VDSM model. The ion channel conductances are set to maintain the resting membrane potential (RMP) at - 50 mV as it is documented that the resting membrane potential (RMP) in VDSM cell varies between - 45 to - 70 mV. AP was simulated in the whole-cell model by applying an external stimulus current (10-30 pA), as a brief square pulse of 10 ms duration. The AP exhibits depolarization, repolarization and hyperpolarization phases as found in experiments. The results show that both L-type Ca2+ channel and Na+ channel play important roles in generating a spike, although both L-type Ca2+ channel is the major contributor to the total inward current. The results also show that both BK and KCNQ channels play an important role in setting RMP and repolarization. Our model, constrained heavily by physiological data, provides a powerful tool to investigate the ionic mechanisms underlying the genesis of VDSM electrical activity, which can further shed light on certain aspects of premature ejaculation and male sexual disorder.