New life in overactive bladder. Focus on “Novel regulatory mechanism in human urinary bladder: central role of transient receptor potential melastatin 4 channels in detrusor smooth muscle function”

Abstract

INDIVIDUALS ARE FACED WITH varying aspects of health problems that have an impact on their quality of life. Suffering a nonfatal heart attack certainly changes one's appreciation of life, which may result in a vigilant awareness of blood pressure, a change in diet, an initiation of an exercise program, a reduction in smoking along with other adjustments of daily life. The severity of a health condition may be manifested in subtle ways, yet have a major impact on quality of life. For many of us, we do not realize the simplicity of normal urinary bladder function. However, overactive bladder syndrome (OAB, also referred to as overactive detrusor function) is a condition that has symptoms of urgency for urination (micturition) with or without urge incontinence, high frequency of urination, and nocturia (waking at night to urinate) (1). OAB has a significant cost to the individual and the healthcare system. Indeed, in 2008, an estimated ϳ11% of the world population was affected by OAB and it was estimated to grow to 20% by 2018 (6). In 2008 alone, it was estimated that the collective direct cost burden for Canada, Germany, UK, Italy, Sweden, and Spain was £3.9 billion, which did not include nursing home costs (7). Other costs of OAB escalate the personal and economic impact when one factors in absenteeism from work and decreased productivity while at work (7). It is obvious that the cost burden of OAB to the quality of life of the individual, the healthcare system, and the workforce is substantial.Generally, our understanding of the reason why OAB is manifested is unknown. The detrusor smooth muscle (DSM) of the wall of the urinary bladder is key to the function of the bladder (1). The cells of the DSM relax during the process of filling and storing urine in the bladder for long periods of time without leakage. Additionally, for urination to occur, the DSM cells must synchronously contract in concert with coordinated function of the internal and external sphincters of the urethra. This integrative function is controlled by neural and hormonal signals (1). In OAB, there can be involuntary contractions of DSM cells during the storage time of urine that results in leakage. There are strategies to reduce the complications of OAB that include life style changes (reduced fluid intake), acupuncture (2), and pharmacological therapy (8). For example, if one could pharmacologically target a specific protein channel involved in membrane potential function of DSM cells with a drug that results in relaxation of the DSM; this would be of great benefit.In this issue of the American Journal Physiology-Cell Physiology, Petkov and colleagues (5) provide a very exciting study in which they report a novel regulatory mechanism in the human urinary bladder in which the transient receptor potential melastatin 4 channel (TRPM4) is instrumental in human DSM excitability and contractility. The implications from their results suggest that TRPM4 may be a novel therapeutic target for ameliorating symptoms of OAB.TRPM4 is a Ca 2ϩ -activated nons...

Regulation of transient receptor potential melastatin 4 channel by sarcoplasmic reticulum inositol trisphosphate receptors: Role in human detrusor smooth muscle function

“…[6][7][8] More recently, we further explored the translational implications of our findings in rodents by investigating the physiologic roles for the TRPM4 channels in clinically-characterized human DSM. 5 As summarized in a recent editorial article in the American Journal of Physiology Cell Physiology, 14 our group revealed critical roles for the TRPM4 channels in regulating DSM function. TRPM4 channel expression is abundant in human DSM and species-related differences in the functional roles of the TRPM4 channels have been reported between human and rodents.…”

“…[6][7][8][11][12][13] We recently provided the first detailed study demonstrating the expression and key functional roles for TRPM4 channels in human DSM excitability and contractility using the selective TRPM4 channel inhibitor 9-phenanthrol. 5 Our novel study was the central topic of an editorial focus in the American Journal of Physiology -Cell Physiology, 14 which highlighted the attractiveness of the TRPM4 channels as potential novel targets for the pharmacological control of the urinary bladder. Under pathophysiological conditions, DSM dysfunction is associated with some forms of overactive bladder.…”

In Silico Electrophysiological Investigation of Transient Receptor Potential Melastatin-4 Ion Channel Biophysics to Study Detrusor Overactivity

“…Hence, accurately quantifying the individual ion channel's contribution to modulating the action potential will aid in exploring more effective drugs for overactive bladder treatment. In recent years, multiple experimental findings have indicated the presence of the TRPM4 ion channel in DSM cells and its role in modulating DSM contraction [49,50]. Due to the highly complex nature of experimental smooth muscle electrophysiology setups, the quantified contribution of the TRPM4 channel to DSM cell membrane potential and action potential has not yet been studied.…”

In Silico Electrophysiological Investigation of Transient Receptor Potential Melastatin-4 Ion Channel Biophysics to Study Detrusor Overactivity

“…Hence, accurately quantifying the individual ion channel's contribution to modulating the action potential will aid the exploration of more effective drugs for overactive bladder treatment. In recent years, multiple experimental findings have indicated the presence of the TRPM4 ion channel in DSM cells and its role in modulating DSM contraction [49,50]. Due to the highly complex nature of experimental smooth muscle electrophysiology setups, the quantified contribution of the TRPM4 channel to DSM cell membrane potential and action potential has not yet been studied.…”

“…In addition, the Ca 2+ -dependent K + channels in DSM cells are categorized into large (BK), intermediate (IK), and small (SK) conductance ion channels [45][46][47][48]. Several research groups have recently conducted an intriguing study revealing a novel regulatory mechanism of the transient receptor potential melastatin 4 (TRPM4) ion channel in modulating DSM cell excitability [49,50]. The TRPM4 channel has been shown to play a crucial role in regulating the resting membrane potential and basal tone of various smooth muscle cells.…”