Cellular origin and regulation of the electrical slow wave in the murine small intestinal musculature

Abstract

<p>The electrical pacemaker slow wave is responsible for the generation of anally propagating phasic contractions underlying the peristaltic motor activity of the gastrointestinal musculature. Yet, the cellular origins of the slow wave and mechanisms of the slow wave regulation or generation still remain unresolved and constituted primary goals of the current thesis. As described in detail in Chapters Three-Six, spontaneously genetic knock out mice with genetic mutations affecting the structure (W / Wν mice), expression (Wbd / Wbd mice), or the ligand (Sl / Sld mice) of the kit tyrosine kinase receptor were shown to lack both the network of interstitial cells of Cajal associated with the myenteric plexus and the slow wave activity in the small intestine, hence, supporting the proposed role of the interstitial cells of Cajal as pacemaker cells responsible for the slow wave generation. In the absence of the slow wave, the mutant musculature was either electrically quiescent or showed action potentials in regular or irregular patterns as recorded with a standard microelectode technique. The observed action potentials were also clearly distinguished from the slow waves by their shape and pharmacological sensitivities to L-type Ca2+ channel and K+ channel blockade. The mechanisms of the slow wave generation and regulation are addressed in Chapters Seven-Nine. The data indicate that the slow wave generation involves primarily Na+ and Ca2+ conductances not mediated by TTX- or mexiletine-sensitive Na+ channels, gadolinium sensitive nonselective cation channels, or L-type Ca2+ channels. Cl- channels may be also involved in the regulation but not in the slow wave initiation. Pharmacological agents acting on cytosolic Ca2+ , SR Ca2+ ATPase, and intracellular Ca 2+ release mechanisms support the role of intracellular Ca 2+ release mechanisms, sensitive to IP3 , in the regulation of the slow wave frequency and amplitude. Furthermore, activation of the Ca 2+ induced Ca2+ release (CICR) mechanism leads to depolarization not mediated predominantly by chloride channels nor likely by KCa channels. The CICR may be also involved in the regulation of the slow wave. These experiments importantly identify intracellular metabolic pathways that may potentially lead to the development of therapeutic approaches aimed at treating certain gastrointestinal motor disorders by modifying the slow wave frequency or amplitude.</p>