The hyperpolarization-activated, cyclic nucleotide-gated channel resides on myocytes in mouse bladders and contributes to adrenergic-induced detrusor relaxation

• DOI: 10.1152/ajpregu.00277.2021
• Publication Date: 2022-05-03T15:49:00Z
• Authors: Fouad Lemtiri-Chlieh; Dylan S. Baker; Iman M. Al-Naggar; Ramalakshmi Ramasamy; George A. Kuchel; Eric S. Levine; Paul Robson; Phillip P. Smith
• Keywords: 0301 basic medicine; Cyclic; JGM; Nucleotides; Life Sciences; Cyclic Nucleotide-Gated Cation Channels; Inbred C57BL; Interstitial Cells of Cajal; Mice, Inbred C57BL; Mice; 03 medical and health sciences; Adrenergic Agents; Medicine and Health Sciences; Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels; Animals; Nucleotides, Cyclic

Control of urinary continence is predicated on sensory signaling about bladder volume. Bladder sensory nerve activity is dependent on tension, implicating autonomic control over detrusor myocyte activity during bladder filling. Hyperpolarization-activated cyclic nucleotide-gated (HCN) ion channels are known contributors to bladder control, but their mechanism of action is not well understood. The lack of a definitive identification of cell type(s) expressing HCN in the bladder presents a significant knowledge gap. We recently reported a complete transcriptomic atlas of the C57BL/6 mouse bladder showing the dominant HCN paralog in mouse bladder, Hcn1, is limited to a subpopulation of detrusor smooth myocytes (DSMs). Here, we report details of these findings, along with results of patch-clamp experiments, immunohistochemistry, and functional myobath/tension experiments in bladder strips. With the use of a transgenic mouse expressing fluorescence-tagged α-smooth muscle actin, our data confirmed location and function of DSM HCN channels. Despite previous associations of HCN with postulated bladder interstitial cells, neither evidence of specific interstitial cell types nor an association of nonmyocytes with HCN was discovered. We confirm that HCN activation participates in reducing sustained (tonic) detrusor tension via cAMP, with no effect on intermittent (phasic) detrusor activity. In contrast, blockade of HCN increases phasic activity induced by a protein kinase A (PKA) blocker or a large-conductance Ca2+-activated K+ (BK) channel opener. Our findings, therefore, suggest a central role for detrusor myocyte HCN in regulating and constraining detrusor myocyte activity during bladder filling.