Ca2+ signalling in urethral interstitial cells of Cajal

Abstract

Interstitial cells of Cajal (ICC) in the urethra have been proposed as specialized pacemakers that are involved in the generation of urethral tone and therefore the maintenance of urinary continence. Recent studies on freshly dispersed ICC from the urethra of rabbits have demonstrated that pacemaker activity in urethra ICC is characterized by spontaneous transient depolarizations (STDs) under current clamp and spontaneous transient inward currents (STICs) under voltage clamp. When these events were simultaneously recorded with changes in intracellular Ca(2+) (using a Nipkow spinning disk confocal microscope) they were found to be associated with global Ca(2+) oscillations. In this short review we will consider some of these recent findings regarding the contribution of intracellular Ca(2+) stores and Ca(2+) influx to the generation of pacemaker activity in urethral ICC with particular emphasis on the contribution of reverse Na(+)/Ca(2+) exchange (NCX).

Figure 1. Pseudo linescan or x,t plot of propagating Ca²⁺ waves in an isolated urethra ICC

Ca²⁺ waves were abolished by removal of Ca_o² (A). Reduction in [Ca²⁺]_o from 1.8 to 0.9 mm reduced the frequency of Ca²⁺ waves by ∼50% (B). An increase in [Ca²⁺]_o to 3.6 mm increased the frequency of Ca²⁺ waves (C). Modified from Sergeant et al. (2006.)

Figure 2. Simultaneous recording of membrane potential in current clamp and [Ca²⁺]_i in a fluo-4 AM loaded urethral ICC, imaged with a Nipkow spinning disk confocal microscope shows that STDs (red) are associated with spontaneous Ca²⁺ oscillations (blue)

In the presence of 10 μm nifedipine the duration of both events is shortened, but their frequency is not affected.

Figure 3. Representative recording from an isolated ICC showing that reduction of [Na⁺]_o from 130 to 13 mm doubles the frequency of spontaneous Ca²⁺ oscillations

Modified from Bradley et al. (2006).

Figure 4. Representative recordings showing the effect of the selective reverse mode NCX inhibitors KB-R7943 and SEA0400 on spontaneous Ca²⁺ oscillations (A and B, respectively) and STICs recorded at −60 mV (C and D, respectively)

Modified from Bradley et al. (2006).

Figure 5. Schematic model of pacemaker activity in isolated urethra ICC

Ca²⁺ release from RyRs (red) is initiated by Ca²⁺ influx via reverse NCX. This in turn causes further release of Ca²⁺ from IP₃Rs (green) which are therefore responsible for propagation of these events. The raised intracellular [Ca²⁺] leads to stimulation of plasmalemmal Ca²⁺-activated Cl⁻ channels causing depolarization of the membrane and activation of L-type Ca²⁺ channels.