A biophysically detailed computational model of urinary bladder small DRG neuron soma

Abstract

Bladder small DRG neurons, which are putative nociceptors pivotal to urinary bladder function, express more than a dozen different ionic membrane mechanisms: ion channels, pumps and exchangers. Small-conductance Ca2+-activated K+(SKCa) channels which were earlier thought to be gated solely by intracellular Ca2+concentration ([Ca]i) have recently been shown to exhibit inward rectification with respect to membrane potential. The effect of SKCainward rectification on the excitability of these neurons is unknown. Furthermore, studies on the role of KCachannels in repetitive firing and their contributions to different types of afterhyperpolarization (AHP) in these neurons are lacking. In order to study these phenomena, we first constructed and validated a biophysically detailed single compartment model of bladder small DRG neuron soma constrained by physiological data. The model includes twenty-two major known membrane mechanisms along with intracellular Ca2+dynamics comprising Ca2+diffusion, cytoplasmic buffering, and endoplasmic reticulum (ER) and mitochondrial mechanisms. Using modelling studies, we show that inward rectification of SKCais an important parameter regulating neuronal repetitive firing and that its absence reduces action potential (AP) firing frequency. We also show that SKCais more potent in reducing AP spiking than the large-conductance KCachannel (BKCa) in these neurons. Moreover, BKCawas found to contribute to the fast AHP (fAHP) and SKCato the medium-duration (mAHP) and slow AHP (sAHP). We also report that the slow inactivating A-type K+channel (slow KA) current in these neurons is composed of 2 components: an initial fast inactivating (time constant ∼ 25-100 ms) and a slow inactivating (time constant ∼ 200-800 ms) current. We discuss the implications of our findings, and how our detailed model can help further our understanding of the role of C-fibre afferents in the physiology of urinary bladder as well as in certain disorders.