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Age-dependent decrease in TRPM4 channel expression but not trafficking alters urinary bladder smooth muscle contractility.

ABSTRACT: During development, maturation, or aging, the expression and function of urinary bladder smooth muscle (UBSM) ion channels can change, thus affecting micturition. Increasing evidence supports a novel role of transient receptor potential melastatin-4 (TRPM4) channels in UBSM physiology. However, it remains unknown whether the functional expression of these key regulatory channels fluctuates in UBSM over different life stages. Here, we examined TRPM4 channel protein expression (Western blot) and the effects of TRPM4 channel inhibitors, 9-phenanthrol and glibenclamide, on phasic contractions of UBSM isolated strips obtained from juvenile (UBSM-J, 5-9 weeks old) and adult (UBSM-A, 6-18 months old) male guinea pigs. Compared to UBSM-J, UBSM-A displayed a 50-70% reduction in total TRPM4 protein expression, while the surface-to-intracellular expression ratio (channel trafficking) remained the same in both age groups. Consistent with the reduced total TRPM4 protein expression in UBSM-A, 9-phenanthrol showed lower potencies and/or maximum efficacies in UBSM-A than UBSM-J for inhibiting amplitude and muscle force of spontaneous and 20 mM KCl-induced phasic contractions. Compared to 9-phenanthrol, glibenclamide also attenuated both spontaneous and KCl-induced contractions, but with less pronounced differential effects in UBSM-A and UBSM-J. In both age groups, regardless of the overall reduced total TRPM4 protein expression in UBSM-A, cell surface TRPM4 protein expression (~80%) predominated over its intracellular fraction (~20%), revealing preserved channel trafficking mechanisms toward the cell membrane. Collectively, this study reports novel findings illuminating a fundamental physiological role for TRPM4 channels in UBSM function that fluctuates with age.

SUBMITTER: Maxwell SE

PROVIDER: S-EPMC7903938 | biostudies-literature | 2021 Feb

REPOSITORIES: biostudies-literature

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Age-dependent decrease in TRPM4 channel expression but not trafficking alters urinary bladder smooth muscle contractility.

Maxwell Sarah E SE Leo M Dennis MD Malysz John J Petkov Georgi V GV

Physiological reports 20210201 4

During development, maturation, or aging, the expression and function of urinary bladder smooth muscle (UBSM) ion channels can change, thus affecting micturition. Increasing evidence supports a novel role of transient receptor potential melastatin-4 (TRPM4) channels in UBSM physiology. However, it remains unknown whether the functional expression of these key regulatory channels fluctuates in UBSM over different life stages. Here, we examined TRPM4 channel protein expression (Western blot) and t ...[more]

PMID: 33625779

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Project description:The muscularis mucosae, a type of smooth muscle located between the urothelium and the urinary bladder detrusor, has been described, although its properties and role in bladder function have not been characterized. Here, using mucosal tissue strips isolated from guinea pig urinary bladders, we identified spontaneous phasic contractions (SPCs) that appear to originate in the muscularis mucosae. This smooth muscle layer exhibited Ca(2+) waves and flashes, but localized Ca(2+) events (Ca(2+) sparks, purinergic receptor-mediated transients) were not detected. Ca(2+) flashes, often in bursts, occurred with a frequency (∼5.7/min) similar to that of SPCs (∼4/min), suggesting that SPCs are triggered by bursts of Ca(2+) flashes. The force generated by a single mucosal SPC represented the maximal force of the strip, whereas a single detrusor SPC was ∼3% of maximal force of the detrusor strip. Electrical field stimulation (0.5-50 Hz) evoked force transients in isolated detrusor and mucosal strips. Inhibition of cholinergic receptors significantly decreased force in detrusor and mucosal strips (at higher frequencies). Concurrent inhibition of purinergic and cholinergic receptors nearly abolished evoked responses in detrusor and mucosae. Mucosal SPCs were unaffected by blocking small-conductance Ca(2+)-activated K(+) (SK) channels with apamin and were unchanged by blocking large-conductance Ca(2+)-activated K(+) (BK) channels with iberiotoxin (IbTX), indicating that SK and BK channels play a much smaller role in regulating muscularis mucosae SPCs than they do in regulating detrusor SPCs. Consistent with this, BK channel current density in myocytes from muscularis mucosae was ∼20% of that in detrusor myocytes. These findings indicate that the muscularis mucosae in guinea pig represents a second smooth muscle compartment that is physiologically and pharmacologically distinct from the detrusor and may contribute to the overall contractile properties of the urinary bladder.

Dataset Information

Age-dependent decrease in TRPM4 channel expression but not trafficking alters urinary bladder smooth muscle contractility.

Publications

Age-dependent decrease in TRPM4 channel expression but not trafficking alters urinary bladder smooth muscle contractility.

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