During pregnancy the uterus undergoes considerable remodelling in preparation for the substantial contractile effort of parturition. We have recently developed a mathematical model for the uterine smooth muscle cell (USMC) in late pregnancy which describes all published, biophysically detailed excitation-contraction coupling parameters from membrane electrophysiology to intracellular Ca2+ dynamics and force production [1]. The model is capable of reproducing many experimental observations including several recorded action potential (AP) forms of variable duration ~0.5-60 secs. However, a restriction of the model is a difficulty in computationally reproducing long duration spike APs that have been experimentally noted [2]. We here use a theoretical modelling approach to investigate whether altered potassium current characteristics may underlie a transition from short- to long duration spike APs. We have systematically searched the parameter space of the 14 USMC electrogenic currents of the model to identify potential components that can change the electrophysiological behaviour of the USMC into longer duration spike APs. No single intrinsic parameter, such as altering individual channel conductance, could do so. However, a combinatorial approach of increasing the activation (2X) and inactivation (10X) time constants, and the conductance (from 0.65 pS/pF to 0.8 pS/pF), of a 4-AP-insensitive voltage-gated K+ current did reproduce experimentally recorded long bursting-type APs [2]. Although this prediction may seem counter intuitive, there are supporting evidences: (i) mRNA expression encoding a protein that functions as a slowly activating potassium current, similar to the cardiac IKs current, has long been suggested to increase in late pregnancy [3]; (ii) IKs consists of the KCNQ voltage-gated channel and KCNE subunits and USMC KCNQ/KCNE transcripts are gestationally regulated [4]; (iii) KCNQ activation time constants and conductance can be increased by co-expression of different KCNE subunits [5]; (iv) our simulations present similar changes in the kinetic properties and conductance of a native voltage-gated K+ current to produce long duration bursting APs frequently observed in USMCs [2]. This leads us to speculate that KCNQ/KCNE channels, or similar, may be important regulators of USMC AP form.
Physiology 2012 (Edinburgh) (2012) Proc Physiol Soc 27, PC355
Poster Communications: Potential role for a potassium current with slow kinetics in regulating uterine smooth muscle action potential configuration: a modelling prediction
W. Tong1, R. M. Tribe2, M. J. Taggart1
1. Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom. 2. Women's Health Academic Centre KHP, King's College London, London, United Kingdom.
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