["The Journal of Physiology, EarlyView. ", "\nAbstract figure legend Pacemaker activity in ICC of human stomach involves a complex series of events including the following:\nCa2+ entry through voltage‐dependent Ca2+ channels in interstitial cells of Cajal (ICC) generates the upstroke depolarization.\nCa2+ entry initiates Ca2+‐induced Ca2+ release from Ca2+ stores in endoplasmic reticulum (ER). Ca2+ release from ER activates Ca2+‐dependent Cl− channels (ANO1) in the plasma membrane (PM), resulting in the sustained depolarization of the plateau phase.\nRecovery of Ca2+ into ER via the sarco/endoplasmic reticulum Ca2+ pump (SERCA) reduces cytoplasmic Ca2+, deactivates ANO1 channels and causes repolarization to the diastolic phase of membrane potential (denoted by 4 in membrane potential trace). Na+/Ca2+ exchange may also cause extrusion of Ca2+ from cells (not shown).\nSlow‐wave depolarizations conduct to electrically coupled smooth muscle cells, causing the activation of L‐type Ca2+ channels, Ca2+ entry and excitation–contraction coupling (not depicted).\n\n\n\n\n\n\n\n\n\nAbstract\nGastric 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 CaV1.2 and CaV1.3 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.\n\n\n\n\n\n\n\n\n\nKey points\n\nWhat is known about gastric electrophysiology is primarily deduced from animal studies and extracellular recordings from human patients.\nIt is difficult to determine the ionic mechanisms underlying components of pacemaker activity from extracellular recordings.\nUsing 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.\nPacemaker 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.\n\n\n"]