Central role of the BK channel in urinary bladder smooth muscle physiology and pathophysiology

Abstract

The physiological functions of the urinary bladder are to store and periodically expel urine. These tasks are facilitated by the contraction and relaxation of the urinary bladder smooth muscle (UBSM), also known as detrusor smooth muscle, which comprises the bladder wall. The large-conductance voltage- and Ca(2+)-activated K(+) (BK, BKCa, MaxiK, Slo1, or KCa1.1) channel is highly expressed in UBSM and is arguably the most important physiologically relevant K(+) channel that regulates UBSM function. Its significance arises from the fact that the BK channel is the only K(+) channel that is activated by increases in both voltage and intracellular Ca(2+). The BK channels control UBSM excitability and contractility by maintaining the resting membrane potential and shaping the repolarization phase of the spontaneous action potentials that determine UBSM spontaneous rhythmic contractility. In UBSM, these channels have complex regulatory mechanisms involving integrated intracellular Ca(2+) signals, protein kinases, phosphodiesterases, and close functional interactions with muscarinic and β-adrenergic receptors. BK channel dysfunction is implicated in some forms of bladder pathologies, such as detrusor overactivity, and related overactive bladder. This review article summarizes the current state of knowledge of the functional role of UBSM BK channels under normal and pathophysiological conditions and provides new insight toward the BK channels as targets for pharmacological or genetic control of UBSM function. Modulation of UBSM BK channels can occur by directly or indirectly targeting their regulatory mechanisms, which has the potential to provide novel therapeutic approaches for bladder dysfunction, such as overactive bladder and detrusor underactivity.

BK channel regulation by phosphodiesterase type 1: a novel signaling pathway controlling human detrusor smooth muscle function

“…Previous studies demonstrated that the activation of mAChRs, the mAChR 3 subtype in particular, leads to an inhibition of BK channel activity in human DSM cells via a Ca 2ϩ -dependent regulatory mechanism (17)(18)(19). In contrast, cAMP-dependent activation of PKA signaling pathways leads to an increase in Ca 2ϩ sparks, BK channel activity, and hyperpolarization of DSM cells, thus decreasing DSM excitability and contractility (8,19,28).…”

“…It is well-established that the large-conductance voltage-and Ca 2ϩ -activated K ϩ (BK) channels are key regulators of DSM excitability and contractility, and therefore are considered as promising novel targets for OAB therapies (19). Depolarization of the DSM cell membrane initiates action potentials, voltage-dependent Ca 2ϩ influx, and spontaneous phasic contractions (19).…”

“…Depolarization of the DSM cell membrane initiates action potentials, voltage-dependent Ca 2ϩ influx, and spontaneous phasic contractions (19). Depolarization of the cell membrane potential along with the Ca 2ϩ influx during an action potential firing also activates BK channels, which provides a negative feedback to attenuate DSM excitability (19). BK channel activity is regulated by localized intracellular Ca 2ϩ release events from the sarcoplasmic reticulum (SR) ryanodine receptors (RyRs), known as "Ca 2ϩ sparks."…”

“…Ca 2ϩ sparks transiently activate BK channels generating transient BK currents (TBKCs) (8,12,16,27,28). TBKCs correspond to transient hyperpolarizations in DSM cells (19). The frequencies of TBKCs and related transient hyperpolarizations are tightly correlated in DSM cells, thus contributing to DSM excitability (28).…”

“…In contrast, cAMP-dependent activation of PKA signaling pathways leads to an increase in Ca 2ϩ sparks, BK channel activity, and hyperpolarization of DSM cells, thus decreasing DSM excitability and contractility (8,19,28).…”