Cholinergic neurotransmission and muscarinic receptors in the enteric nervous system

The effects of agonists and antagonists of nicotinic, muscarinic (M1 and M2), and adrenergic receptors on migrating spike complexes (MSC) in ileum of fasting cats are reported. Hexamethonium decreased MSC frequency and blocked propagation. Atropine at low concentrations increased MSC frequency and increased velocity of propagation; atropine at high concentration blocked propagation. Pirenzepine (Pz; M1 antagonist) increased MSC frequency and propagation velocity. McNeil A-343 (M1 agonist), by a Pz-sensitive phentolamine-insensitive mechanism, and 4-diethylamine-methylpiperidine (4-DAMP; M2 antagonist) blocked propagation of an ongoing MSC but had no significant effect on frequency or velocity. Bethanechol (M2-receptor agonist) increased phasic spiking by a 4-DAMP-sensitive mechanism and blocked MSC propagation by a Pz-sensitive mechanism. Phenylephrine (alpha 1-adrenoceptor agonist) or oxymetazoline (alpha 2-adrenoceptor agonist) blocked MSC propagation but had no effect on MSC frequency or velocity. Phentolamine (nonselective alpha 1-adrenoceptor antagonist), prazosin (alpha 1-adrenoceptor antagonist), or yohimbine (alpha 2-adrenoceptor antagonist) alone had no effect on MSC activity. The conclusion is that the enteric nervous system controls and regulates the MSC by the following proposed mechanisms. 1) M1-muscarinic receptors, located either on postganglionic inhibitory neurons or presynaptically at a nicotinic synapse and/or neuromuscular junction, are involved in the tonic inhibitory control of MSC initiation and propagation. 2) Nicotinic and M2 muscarinic receptors, located on excitatory postganglionic motoneurons and smooth muscle cells, respectively, are important in the initiation and/or propagation of MSC. 3) alpha 1-Adrenoceptors on the smooth muscle cells and alpha 2-adrenoceptors located presynaptically at the nicotinic ganglionic synapses are not tonically active but inhibit MSC activity (4). Smooth muscle beta-adrenoceptors do not play a significant role in neural control of MSC activity.

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Cholinergic activation of enteric glia is a physiological mechanism that contributes to the regulation of gastrointestinal motility

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.00155.2018 ◽

2018 ◽

Vol 315 (4) ◽

pp. G473-G483 ◽

Cited By ~ 14

Author(s):

Ninotchska M. Delvalle ◽

David E. Fried ◽

Gretchen Rivera-Lopez ◽

Luke Gaudette ◽

Brian D. Gulbransen

Keyword(s):

Nervous System ◽

Enteric Nervous System ◽

Muscarinic Receptors ◽

Gastrointestinal Motility ◽

Physiological Mechanism ◽

Receptor Activation ◽

Glial Activation ◽

Enteric Neurons ◽

Enteric Glia ◽

Physiological Regulation

The reflexive activities of the gastrointestinal tract are regulated, in part, by precise interactions between neurons and glia in the enteric nervous system (ENS). Intraganglionic enteric glia are a unique type of peripheral glia that surround enteric neurons and regulate neuronal function, activity, and survival. Enteric glia express numerous neurotransmitter receptors that allow them to sense neuronal activity, but it is not clear if enteric glia monitor acetylcholine (ACh), the primary excitatory neurotransmitter in the ENS. Here, we tested the hypothesis that enteric glia detect ACh and that glial activation by ACh contributes to the physiological regulation of gut functions. Our results show that myenteric enteric glia express both the M3 and M5 subtypes of muscarinic receptors (MRs) and that muscarine drives intracellular calcium (Ca2+) signaling predominantly through M3R activation. To elucidate the functional effects of activation of glial M3Rs, we used GFAP::hM3Dq mice that express a modified human M3R (hM3Dq) exclusively on glial fibrillary acidic protein (GFAP) positive glia to directly activate glial hM3Dqs using clozapine- N-oxide. Using spatiotemporal mapping analysis, we found that the activation of glial hM3Dq receptors enhances motility reflexes ex vivo. Continuous stimulation of hM3Dq receptors in vivo, drove changes in gastrointestinal motility without affecting neuronal survival in the ENS and glial muscarinic receptor activation did not alter neuron survival in vitro. Our results provide the first evidence that GFAP intraganglionic enteric glia express functional muscarinic receptors and suggest that the activation of glial muscarinic receptors contributes to the physiological regulation of functions. NEW & NOTEWORTHY Enteric glia are emerging as novel regulators of enteric reflex circuits, but little is still known regarding the effects of specific transmitter pathways on glia and the resulting consequences on enteric reflexes. Here, we provide the first evidence that enteric glia monitor acetylcholine in the enteric nervous system and that glial activation by acetylcholine is a physiological mechanism that contributes to the functional regulation of intestinal reflexes.

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