Fig. 20: Proposed regulatory influence of ICC-SS on longitudinal muscle excitability.

Colonic ICC-SS fire Ca²⁺ transients from ER stores via IP₃Rs. Maintaining Ca²⁺ transients requires ER refilling by SOCE (via Orai channels) and SERCA. Ca²⁺ release activates Ano1 and Cl⁻ efflux, leading to ICC-SS depolarization. Depolarization is conducted to LSMCs via gap junctions and increases the open probability of voltage-dependent Cav_1.2 channels, leading to action potentials, Ca²⁺ influx and rapidly propagating Ca²⁺ waves and excitation-contraction coupling (EC) in LSMC bundles. NO released from nNOS⁺ enteric inhibitory motor neurons modulates the activity of ICC-SS and LSMC by activating sGC and inhibiting Ca²⁺ release in ICC-SS. LSMC also fire intracellular Ca²⁺ waves that are not affected by Ano1 and Cav_1.2 channels and are not linked to E-C coupling. These likely represent Ca²⁺ signals that activate large K⁺ channels (BK) in SMCs that serve to maintain negative resting potentials in LSMCs.