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 SKCa inward rectification on the excitability of these neurons is unknown. Furthermore, studies on the role of KCa channels 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 SKCa is an important parameter regulating neuronal repetitive firing and that its absence reduces action potential (AP) firing frequency. We also show that SKCa is more potent in reducing AP spiking than the large-conductance KCa channel (BKCa) in these neurons. Moreover, BKCa was found to contribute to the fast AHP (fAHP) and SKCa to 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.
Highlights
The sensory component of the reflex pathway of the bladder is formed by the dorsal root ganglion (DRG) neurons
Using our elaborate, validated model of bladder small DRG neuron soma, we addressed certain outstanding questions regarding the factors that govern the functioning of these neurons and showed the following: (1) the inward rectifying property of small-conductance K+ Channels (KCa) (SKCa) channels increases the excitability of bladder small DRG neurons, (2) BKCa may contribute to the fast AHP (fAHP) of the spike while SKCa may contribute to to the medium duration AHP (mAHP) and slow AHP (sAHP), (3) SKCa channels are more potent in suppressing action potential (AP) firing than BKCa channels, (4) the slow-inactivating KA (slow KA) currents are composed of 2 inactivation components: a fast component and a slower component which in turn could be the result of 2 different molecular constituents of the channel
By exercising our model in appropriate ways we were able to (i) corroborate our hypothesis concerning the effect of inwardly rectifying SKCa channels on neuronal excitability; (ii) gain several insights into the roles of BKCa and SKCa channels in bladder small DRG neuron such as the contributions of these channels to the genesis of different types of AHP and the relative efficacies of BKCa and SKCa channels in the regulation of repetitive firing in these neurons, casting light on hitherto unresolved biological questions
Summary
The sensory component of the reflex pathway of the bladder is formed by the dorsal root ganglion (DRG) neurons. Afferent signals such as bladder pressure, volume, temperature, pH, presence of irritants and pain are transmitted to the spinal cord via these neurons. Biophysical changes at the axon terminals in the bladder and at the spinal cord as well as the alterations in the soma located in the DRG are major factors that may under certain conditions contribute to urinary bladder pathophysiology. The small DRG neurons are generally considered nociceptors i.e. they convey information related to pain. They may take up the function of A-δ fibres Significant changes in bladder small DRG neurons have been reported in various conditions such as bladder inflammation (interstitial cystitis), spinal cord injury (SCI), bladder overactivity, bladder outlet obstruction and hyperexcitability [3, 5, 9, 10]
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