Fig. 15. Ca²⁺ signaling drives pacemaker activity in gastric ICC-MY.

Steps in Ca²⁺ signaling in relation to generation of slow waves in gastric muscles are shown. For clarity the various proteins functioning during the slow wave cycle appear in panels at the stages where they become functional. 1. During the inter-slow wave interval, Ca²⁺ release from ER causes Ca²⁺ transients that activate Ano1 channels in the plasma membrane (PM). Activation of Ano1 causes development of spontaneous transient inward currents (STICs) which have depolarizing influence and generate spontaneous transient depolarizations (STDs). 2. Slow wave upstroke. The depolarization from STDs activates T-type Ca²⁺ current (VDCC1) that rapidly depolarize ICC-MY close to 0 mV. Influx of Ca²⁺ contributes to activation of Ano1 channels. 3. Plateau phase. Depolarization caused by the slow wave upstroke activates L-type Ca²⁺ current (VDCC2). Ca²⁺ entry causes localized Ca²⁺ induced Ca²⁺ release, and a multitude of Ca²⁺ release sites leads to development of CTCs. Ca²⁺ transient during CTCs activate Ano1 channels and maintain the depolarized state during the plateau phase. 4. Repolarization. When stores are depleted, Ca²⁺ transients cease and the open probability of Ano1 channels decreases to low levels causing repolarization. Repolarization also causes deactivation of VDCCs. SOCE (not shown) and SERCA pumps restore store Ca²⁺ to reset the mechanism for the next slow wave cycle. Corpus and antrum ICC-MY both manifest intrinsic pacemaker activity, however the frequency of pacemaking in the corpus is higher than in antrum. The present study suggests that the major difference between the pacemakers in the corpus and antrum is that the probability of Ca²⁺ transient firing is higher in corpus ICC-MY than in antrum. It should also be noted that scheme illustrated in the figure is relevant only to Ca²⁺ transients and activation of conductances in ICC. In intact muscles ICC are electrically coupled to SMCs. Electrical activity is recorded typically from SMCs, so additional conductances contribute to the shaping of the waveforms of slow waves. For example, the rapid repolarization following the initial upstroke (see Fig. 1C) is due to activation of an A-type current in SMCs [86, 87].