Mechanisms responsible for pacemaker activity in human gastric muscles

Gastric muscles were obtained from obese patients with no other underlying morbidities undergoing vertical sleeve gastrectomy (VSG). Quantitative electrophysiological techniques were used to characterize the ionic mechanisms underlying electrical slow waves in muscles of the gastric antrum. Thin muscular sheets were prepared using vibratome sectioning to characterize the electrical activity through the thickness of the tunica muscularis. Two distinct pacemaker regions were identified: large-amplitude, long-duration slow waves occurred at low frequency in longitudinal muscle (LM) near the serosa; higher-frequency, shorter-duration slow waves were recorded in muscle near the myenteric plexus and throughout the circular muscle (CM). The higher-frequency pacemaker dominated activity and generated phasic contractions in intact muscles. The upstroke depolarization of slow waves depended predominantly on T-type Ca²⁺ channels, but Ca_V1.2 and Ca_V1.3 L-type channels also participated. Ca²⁺ entry during the upstroke appeared to initiate Ca²⁺-induced Ca²⁺ release that was sustained for several seconds, activating Ca²⁺-activated Cl^- channels (ANO1). Ca²⁺ release occurred from stores loaded by sarco/endoplasmic reticulum Ca²⁺-ATPase (SERCA), and both IP₃ and ryanodine receptors were involved in the Ca²⁺ release that activated ANO1. The elevation of intracellular Ca²⁺ required to maintain the activation of ANO1 channels through the plateau phase relied upon sustained Ca²⁺ entry through L-type Ca²⁺ channels and Na⁺/Ca²⁺ exchange operating in reverse mode. Stores of Ca²⁺ were maintained over time by store-operated Ca²⁺ entry mediated by ORAI. Slow waves generated the phasic contractions underlying gastric peristalsis. Thus this study provides mechanistic information about the electrophysiology underlying gastric motility. KEY POINTS: What is known about gastric electrophysiology is primarily deduced from animal studies and extracellular recordings from human patients. It is difficult to determine the ionic mechanisms underlying components of pacemaker activity from extracellular recordings. Using quantitative intracellular microelectrode recordings two distinct pacemaker regions were identified in the human gastric antrum: large, long-duration, low-frequency slow waves in the longitudinal muscle and higher-frequency, shorter-duration slow waves near the myenteric plexus and throughout the circular muscle. The higher-frequency pacemaker dominated activity and generated phasic contractions in intact muscles. Pacemaker activity involved a complex series of events, including (i) Ca²⁺ entry through voltage-dependent Ca²⁺ channels, (ii) Ca²⁺ release from intracellular sarco/endoplasmic reticulum Ca²⁺-ATPase stores, (iii) activation of ANO1 and (iv) sustained increase in intracellular Ca²⁺ via a Na⁺/Ca²⁺ exchanger operating in reverse mode.