Role of acid-sensing ion channels in bladder sensory signaling

(PLEASE KEEP IN WORD, DO NOT PDF)
The urinary bladder is a common source of visceral pain, one of the most frequent reasons why patients seek medical attention. Despite the primordial role that afferent pathways have in normal bladder sensation and nociception, we have limited understanding of the molecular events contributing to these processes. This proposal aims to understand the mechanisms by which acid-sensing ion channels (ASICs) regulate bladder afferent signaling. The proposal builds on the findings that the loss of ASIC3 in naïve mice reduces the intravesical pressure required to trigger micturition, while in the setting of chemically-induced cystitis it results in the hyperactivation of nociceptive pathways and chronic pain. These findings are puzzling, because ASICs are presumably responsible for the transduction of extracellular pH transients into electrical signals at the peripheral terminal of bladder afferents. Our working hypothesis is that ASICs control afferent outflow by triggering spike adaptation. We posit that Na+ influx through ASICs initiates a cascade of events that results in the activation of small conductance Ca2+-activated K+ (SK) channels and adaptation. Experiments proposed in Aim 1 will define whether ASICs regulate afferent firing through a mechanism mediated by Ca2+. To test our model, we will use sensory neuron conditional Asic3 knockout mice, Ca2+ imaging, patch-clamp analysis, single-unit recordings, and a collection of pharmacological tools. In Aim 2, we will evaluate whether ASICs and SK channels work in concert to control bladder afferent discharge during sustained stimulation. To assess this, we will use physiological tools in combination with genetic and pharmacological manipulations. Upon completion of these studies, we will have gained a thorough understanding of mechanisms that mediate the adaptation of visceral afferents.

Grant Number: 5R01DK134431-03
NIH Institute/Center: NIH
Principal Investigator: Marcelo Carattino