The T-type calcium channel Ca V 3.2 regulates bladder afferent responses to mechanical stimuli

Luke Grundy, Cindy Tay, Stewart Christie, Andrea M. Harrington, Joel Castro, Fernanda C. Cardoso, Richard J. Lewis, Vladimir Zagorodnyuk, Stuart M. Brierley

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The bladder wall is innervated by a complex network of afferent nerves that detect bladder stretch during filling. Sensory signals, generated in response to distension, are relayed to the spinal cord and brain to evoke physiological and painful sensations and regulate urine storage and voiding. Hyperexcitability of these sensory pathways is a key component in the development of chronic bladder hypersensitivity disorders including interstitial cystitis/bladder pain syndrome and overactive bladder syndrome. Despite this, the full array of ion channels that regulate bladder afferent responses to mechanical stimuli have yet to be determined. Here, we investigated the role of low-voltage-activated T-type calcium (Ca V3) channels in regulating bladder afferent responses to distension. Using single-cell reverse-transcription polymerase chain reaction and immunofluorescence, we revealed ubiquitous expression of Ca V3.2, but not Ca V3.1 or Ca V3.3, in individual bladder-innervating dorsal root ganglia neurons. Pharmacological inhibition of Ca V3.2 with TTA-A2 and ABT-639, selective blockers of T-type calcium channels, dose-dependently attenuated ex-vivo bladder afferent responses to distension in the absence of changes to muscle compliance. Further evaluation revealed that Ca V3.2 blockers significantly inhibited both low- and high-threshold afferents, decreasing peak responses to distension, and delayed activation thresholds, thereby attenuating bladder afferent responses to both physiological and noxious distension. Nocifensive visceromotor responses to noxious bladder distension in vivo were also significantly reduced by inhibition of Ca V3 with TTA-A2. Together, these data provide evidence of a major role for Ca V3.2 in regulating bladder afferent responses to bladder distension and nociceptive signalling to the spinal cord.

Original languageEnglish
Pages (from-to)1012-1026
Number of pages15
Issue number5
Early online date21 Oct 2022
Publication statusPublished - 1 May 2023


  • Bladder
  • Afferent
  • Distension
  • Cav3.2
  • Nociception
  • Pain


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