Alterations in gap junction connexin43/connexin45 ratio mediate a transition from quiescence to excitation in a mathematical model of the myometrium

Abstract

The smooth muscle cells of the uterus contract in unison during delivery. These cells achieve coordinated activity via electrical connections called gap junctions which consist of aggregated connexin proteins such as connexin43 and connexin45. The density of gap junctions governs the excitability of the myometrium (among other factors). An increase in gap junction density occurs immediately prior to parturition. We extend a mathematical model of the myometrium by incorporating the voltage-dependence of gap junctions that has been demonstrated in the experimental literature. Two functional subtypes exist, corresponding to systems with predominantly connexin43 and predominantly connexin45, respectively. Our simulation results indicate that the gap junction protein connexin45 acts as a negative modulator of uterine excitability, and hence, activity. A network with a higher proportion of connexin45 relative to connexin43 is unable to excite every cell. Connexin45 has much more rapid gating kinetics than connexin43 which we show limits the maximum duration of a local burst of activity. We propose that this effect regulates the degree of synchronous excitation attained during a contraction. Our results support the hypothesis that as labour approaches, connexin45 is downregulated to allow action potentials to spread more readily through the myometrium.