Role of potassium ion channels in detrusor smooth muscle function and dysfunction

Abstract

Contraction and relaxation of the detrusor smooth muscle (DSM), which makes up the wall of the urinary bladder, facilitates the storage and voiding of urine. Several families of K(+) channels, including voltage-gated K(+) (K(V)) channels, Ca(2+)-activated K(+) (K(Ca)) channels, inward-rectifying ATP-sensitive K(+) (K(ir), K(ATP)) channels, and two-pore-domain K(+) (K(2P)) channels, are expressed and functional in DSM. They control DSM excitability and contractility by maintaining the resting membrane potential and shaping the action potentials that determine the phasic nature of contractility in this tissue. Defects in DSM K(+) channel proteins or in the molecules involved in their regulatory pathways may underlie certain forms of bladder dysfunction, such as overactive bladder. K(+) channels represent an opportunity for novel pharmacological manipulation and therapeutic intervention in human DSM. Modulation of DSM K(+) channels directly or indirectly by targeting their regulatory mechanisms has the potential to control urinary bladder function. This Review summarizes our current state of knowledge of the functional role of K(+) channels in DSM in health and disease, with special emphasis on current advancements in the field.

Figure 1

Illustration of the transmembrane architecture and subunit stoichiometry of the K⁺ channel types expressed in detrusor smooth muscle cells. K_ir channels (represented by the K_ATP channel) have the simplest K⁺ channel structure, with two transmembrane segments (S) connected by a pore loop. Four such subunits form a functional tetrameric channel pore. K_2P channels form a tetrameric pore structure from two subunits each containing two pore loops. K_V channel subunits have six transmembrane segments with a voltage sensor in the S4 transmembrane domain. BK channels consist of four pore-forming α-subunits and the four regulatory β1 or β4 subunits. Abbreviations: BK channels, large-conductance voltage-activated and Ca²⁺-activated K⁺ channels; K_2P channels, two-pore-domain K⁺ channels; K_ATP channels, inward-rectifying ATP-sensitive K⁺ channels; K_ir channels, inward-rectifying K⁺ channels; K_V channels, voltage-gated K⁺ channels.

Figure 2

Schematic illustration of the detrusor smooth muscle action potential and the roles of various K⁺ channels in determining resting membrane potential and action potential. BK, K_V, K_2P, and probably K_ATP channels determine the resting membrane potential. BK and K_V channels contribute to the initial repolarization phase of the action potential. SK and K_V channels contribute to the prolonged after-hyperpolarization phase of the action potential. Abbreviations: BK channels, large-conductance voltage-activated and Ca²⁺-activated K⁺ channels; Ca_V channels, voltage-gated Ca²⁺ channels; K_2P channels, two-pore-domain K⁺ channels; K_ATP channels, inward-rectifying ATP-sensitive K⁺ channels; K_V channels, voltage-gated K⁺ channels; SK channel, small-conductance Ca²⁺-activated K⁺ channel.

Figure 3

Hypothetical pharmacological dissection of K_Ca and K_V currents in detrusor smooth muscle cells using various K⁺ channel-selective inhibitors. The current trace is an original patch-clamp recording of a whole-cell current from a guinea pig detrusor smooth muscle cell elicited in response to depolarization voltage-step. The initial inward L-type Ca_V current provides Ca²⁺ for the activation of the K_Ca currents. Ryanodine is an inhibitor of the ryanodine receptor, iberiotoxin is a BK channel inhibitor, apamin is an SK channel inhibitor, stromatoxin 1 is a K_V2 channel inhibitor, and E-4031 is a K_V11.1 channel inhibitor. Abbreviations: BK, large-conductance voltage-activated and Ca²⁺-activated K⁺ channel; Ca_V, voltage-gated Ca²⁺ channels; K_Ca, Ca²⁺-activated K⁺ channel; K_V, voltage-gated K⁺ channel; SK, small-conductance Ca²⁺-activated K⁺ channel; TBKCs, transient BK currents.

Figure 4

Schematic illustration of the functional coupling between the β3-AR and the BK channel in a detrusor smooth muscle cell. The BK channels control the opening and closing of the L-type Ca_V channels by depolarizing or hyperpolarizing the cell membrane, thus regulating the global Ca²⁺ influx and spontaneous phasic contractions. BK channels are activated by localized Ca²⁺ signals (‘Ca²⁺ sparks’) caused by Ca²⁺ release from the RyRs of the SR, adjacent to the cell membrane. Stimulation of the β3-AR with selective agonists leads to PKA activation, PLN phosphorylation, and activation of the SR Ca²⁺-pump and RyRs, which causes an increase in Ca²⁺ spark and TBKC activity. The increased TBKC frequency results in a sustained membrane hyperpolarization, closure of the L-type Ca_V channels, reduction in the global Ca²⁺ concentration, and detrusor smooth muscle relaxation. When Ca²⁺ sparks are blocked with ryanodine and/or thapsigargin (an SR Ca²⁺-pump inhibitor), the functional coupling between β3-ARs and BK channels is disrupted. Abbreviations: β3-AR, β3 adrenergic receptor; BK channel, large-conductance voltage-activated and Ca²⁺-activated K⁺ channel; PKA, protein kinase A; PLN, phospholamban; RyR, ryanodine receptor; SR, sarcoplasmic reticulum; TBKC, transient BK current.