Electrical slow waves in the small intestine are generated by pacemaker cells called interstitial cells of Cajal. Drumm et al. record clusters of Ca2+ transients in these cells that are entrained by voltage-dependent Ca2+ entry and which define the duration of the electrical slow waves.

Zhu MH, Sung TS, O'Driscoll K, Koh SD, Sanders KM. Intracellular Ca 2ϩ release from endoplasmic reticulum regulates slow wave currents and pacemaker activity of interstitial cells of Cajal. Am

Non-technical summary Interstitial cells of Cajal (ICC) are tightly associated with excitatory and inhibitory motor neurons in the gastrointestinal tract, and these cells are also connected electrically to smooth muscle cells. We have suggested that ICC participate in responses to neurotransmitters released from neurons that drive motility and help move nutrients and wastes through the gut. We studied responses of isolated ICC to cholinergic neurotransmitter and found that a Ca 2+ -activated Cl − current is activated in ICC in response to cholinergic stimulation. Such a current would result in depolarization that could be conducted to surrounding smooth muscle cells by the electrical connections. Exciting ICC would cause generalized excitation of the smooth muscle tissue. A different conductance is activated in smooth muscle cells by cholinergic stimulation. We tested drugs that blocked the Cl − current in ICC and found that responses to nerve stimulation in intact intestinal muscles were blocked by these drugs. This suggests that ICC mediate electrical responses to cholinergic nerve stimulation. In some human gastrointestinal motility disorders, ICC are damaged or lost. If these cells provide responses to neurotransmitters, this might provide an explanation for motor dysfunction in the gut.Abstract Interstitial cells of Cajal (ICC) provide pacemaker activity and functional bridges between enteric motor nerve terminals and gastrointestinal smooth muscle cells. The ionic conductance(s) in ICC that are activated by excitatory neural inputs are unknown. Transgenic mice (Kit copGFP/+ ) with constitutive expression of a bright green fluorescent protein were used to investigate cellular responses of ICC to cholinergic stimulation. ICC displayed spontaneous transient inward currents (STICs) under voltage clamp that corresponded to spontaneous transient depolarizations (STDs) under current clamp. STICs reversed at 0 mV when E Cl = 0 mV and at -40 mV when E Cl was -40 mV, suggesting the STICs were due to a chloride conductance. Carbachol (CCh, 100 nM and 1 μM) induced a sustained inward current (depolarization in current clamp) and increased the amplitude and frequency of STICs and STDs. CCh responses were blocked by atropine (10 μM) or 4-DAMP (100 nM), an M 3 receptor antagonist. STDs were blocked by niflumic acid and 5-nitro-2-(3-phenylpropylamino)-benzoic acid (both 100 μM), and CCh had no effect in the presence of these drugs. The responses of intact circular muscles to CCh and stimulation of intrinsic excitatory nerves by electrical field stimulation (EFS) were also compared. CCh (1 μM) caused atropine-sensitive depolarization and increased the maximum depolarization of slow waves. Similar atropine-sensitive responses were elicited by stimulation of intrinsic excitatory neurons. Niflumic acid (100 μM) blocked responses to EFS but had minor effect on responses to exogenous CCh. These data suggest that different ionic conductances are responsible for electrical responses elicited by bath-applied CCh and cholinergic ne...

These results concur largely with the characteristic features of IBS, visceral hypersensitivity and altered defecation pattern in the absence of detectable disease, suggesting that this animal model is a methodologically convenient and useful model for studying a subset of IBS.

Enteric motor neurotransmission is essential for normal gastrointestinal (GI) motility. Controversy exists regarding the cells and ionic conductance(s) that mediate post-junctional neuroeffector responses to motor neurotransmitters. Isolated intramuscular ICC (ICC-IM) and smooth muscle cells (SMCs) from murine fundus muscles were used to determine the conductances activated by carbachol (CCh) in each cell type. The calcium-activated chloride conductance (CaCC), anoctamin-1 (Ano1) is expressed by ICC-IM but not resolved in SMCs, and CCh activated a Cl conductance in ICC-IM and a non-selective cation conductance in SMCs. We also studied responses to nerve stimulation using electrical-field stimulation (EFS) of intact fundus muscles from wild-type and Ano1 knockout mice. EFS activated excitatory junction potentials (EJPs) in wild-type mice, although EJPs were absent in mice with congenital deactivation of Ano1 and greatly reduced in animals in which the CaCC-Ano1 was knocked down using Cre/loxP technology. Contractions to cholinergic nerve stimulation were also greatly reduced in Ano1 knockouts. SMCs cells also have receptors and ion channels activated by muscarinic agonists. Blocking acetylcholine esterase with neostigmine revealed a slow depolarization that developed after EJPs in wild-type mice. This depolarization was still apparent in mice with genetic deactivation of Ano1. Pharmacological blockers of Ano1 also inhibited EJPs and contractile responses to muscarinic stimulation in fundus muscles. The data of the present study are consistent with the hypothesis that ACh released from motor nerves binds muscarinic receptors on ICC-IM with preference and activates Ano1. If metabolism of acetylcholine is inhibited, ACh overflows and binds to extrajunctional receptors on SMCs, eliciting a slower depolarization response.