The T-type calcium channel CaV3.2 regulates bladder afferent responses to mechanical stimuli

Abstract

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 V 3) channels in regulating bladder afferent responses to distension. Using single-cell reverse-transcription polymerase chain reaction and immunofluorescence, we revealed ubiquitous expression of Ca V 3.2, but not Ca V 3.1 or Ca V 3.3, in individual bladder-innervating dorsal root ganglia neurons. Pharmacological inhibition of Ca V 3.2 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 V 3.2 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 V 3 with TTA-A2. Together, these data provide evidence of a major role for Ca V 3.2 in regulating bladder afferent responses to bladder distension and nociceptive signalling to the spinal cord.

BCG induced lower urinary tract symptoms during treatment for NMIBC—Mechanisms and management strategies

“…Pre-clinical studies of bladder sensory signaling in health and disease have identified multiple potential therapeutic targets that are highly expressed on bladder-innervating sensory nerves, including voltage gated sodium and calcium channels, various TRP channels, and P2X receptors amongst others (Vlaskovska et al, 2001 ; Grundy et al, 2018b , c , 2023 ; Vanneste et al, 2021 ; Ramsay et al, 2023 ). Crucially, these targets are not commonly expressed on immune cells or known to influence inflammation, and have been shown to inhibit bladder sensory signaling following intravesical instillation, limiting the opportunity for side effects.…”

Current Drug Development Overview: Targeting Voltage-Gated Calcium Channels for the Treatment of Pain

“…Still regarding piperidine derivatives, TTA-P2 is a recently synthesized selective and potent Cav3 inhibitor that was demonstrated to reduce pain responses in mice in acute inflammatory pain and diabetic neuropathy [136][137][138]. In the same perspective, TTA-A2 efficiently inhibits Cav3, demonstrating higher potency for Cav3.2, and it was shown to decrease pain in an irritable bowel syndrome model [139], nocifensive visceromotor responses to noxious bladder distension [140], and bortezomibinduced peripheral neuropathy [141]. Z944 is a piperazine-based and T-type selective antagonist that was also proven to decrease nociception in inflammatory acute and chronic pain states [142] as well as in a trigeminal neuralgia model [143] when injected systemically.…”

An adeno‐associated viral labeling approach to visualize the meso‐ and microanatomy of mechanosensory afferents and autonomic innervation of the rat urinary bladder

“…2 The function of these myelinated neurons has been characterized extensively in electrophysiological studies that have provided important insights into adequate stimuli, firing properties and modulatory mechanisms in groups of mechanosensitive afferents or isolated terminals. [3][4][5][6][7][8][9][10][11][12] Visualization of afferent terminal endings is a powerful strategy for further functional classification and understanding signal transduction at the nerve-organ interface. This is exemplified by skin afferents that comprise a large diversity of structural and functional classes.…”

“…In the urinary bladder, lightly myelinated (A‐delta) afferents have a major role in mechanosensory signaling that is essential for initiating micturition 2 . The function of these myelinated neurons has been characterized extensively in electrophysiological studies that have provided important insights into adequate stimuli, firing properties and modulatory mechanisms in groups of mechanosensitive afferents or isolated terminals 3–12 …”