ReviewPharmacology of synaptic transmission in the enteric nervous system
Introduction
The enteric nervous system (ENS) consists of the myenteric and submucosal plexuses. The myenteric plexus primarily controls contraction and relaxation of gastrointestinal smooth muscle [1]. The submucosal plexus controls the secretory and absorptive functions of the gastrointestinal epithelium, local blood flow and neuroimmune function [2]. Both plexuses receive synaptic inputs from nerve fibres of the sympathetic and parasympathetic divisions of the autonomic nervous system that originate outside the intestine 3., 4., and from sensory nerves that originate in spinal sensory and nodose ganglia [5]. However, most of the synaptic inputs to enteric neurons come from other enteric neurons. The pharmacology of several of these synaptic inputs is the subject of this review.
There are two types of neuron in the ENS: ‘S’ neurons and ‘AH’ neurons 6., 7.. Single electrical stimuli applied to interganglionic connectives elicit fast excitatory postsynaptic potentials (fEPSPs) in S neurons, which are interneurons and motoneurons 1., 8•.. Some AH neurons receive fast synaptic input [9•] but most receive only slow excitatory synaptic input [7]. The action potential in AH neurons has a prominent shoulder that is due to a calcium current and, as a result, the somal action potential is only partly blocked by tetrodotoxin. The action potential is followed by an afterhyperpolarization that lasts 1–20 s. [7]. The afterhyperpolarization is mediated by a calcium-dependent potassium channel, which is activated by calcium entry into the neuron during the action potential [7]. Under resting conditions, AH neurons fire one or two action potentials as the afterhyperpolarization limits the firing rate. Data from functional and neuroanatomical studies indicate that these neurons are intrinsic sensory neurons 7., 8•..
There are multiple mechanisms of synaptic transmission in the ENS. Many synaptic responses are mediated through receptors belonging to the superfamily of G-protein-coupled receptors (GPCRs). In general, GPCRs mediate slow-developing but long-lasting changes in the excitability of enteric neurons, as occurs during slow excitatory postsynaptic potentials (sEPSPs) in S and AH neurons. Trains of high frequency electrical stimuli (5–20 Hz) are usually required to elicit sEPSPs [10]. However, sustained slow post-synaptic excitation is also elicited in AH neurons by long trains (> 1 min) of low frequency stimulation [11]. The transmitter(s) mediating this excitation are not known. All sEPSPs have a long latency (often more than 50 ms) between the time of nerve stimulation and the onset of the response, and a long duration (seconds to minutes). The prolonged latency and duration occur because sEPSPs are mediated through the multi-step signaling processes activated GPCRs 12., 13.. These intracellular signaling mechanisms include the pathways dependent on adenylate cyclase and protein kinase A and the pathways dependent on phospholipase C, diacylglycerol and protein kinase C 12., 13.. Activation of these pathways results in a long-lasting membrane depolarization and an increase in neuronal excitability. The sEPSP, or a response caused by substances that mimic the sEPSP, is due to a simultaneous decrease in potassium conductances that are active at rest and an increase in either chloride conductance in myenteric neurons 10., 14., 15. or cation conductance in submucous neurons [16]. The relative contribution of each conductance change can vary among neurons but most sEPSPs are due to multiple conductance changes even when a net conductance increase or decrease is measured 14., 16..
Rapid neurotransmission through the generation of fEPSPs is a second mechanism of synaptic transmission in the ENS. Fast synaptic responses are mediated through ligand-gated ion channels. These channels are receptor–ion-channel complexes that do not require the generation of intracellular second messenger molecules to convey the primary signal. The neurotransmitter binds to its receptor causing a conformational change that results in a rapid increase in conductance of one or more ions through the ion-channel complex 6., 17..
Section snippets
Nicotinic acetylcholine receptors
Acetylcholine acting on nicotinic acetylcholine receptors (nAChRs) is a prominent mechanism of excitatory neurotransmission in the ENS as demonstrated when fEPSPs recorded from enteric neurons were inhibited by two nAChR antagonists, hexamethonium and mecamylamine 6., 17.. Neuronal nAChRs are composed of a combination of α and β subunits, and the properties of different nAChR subtypes are determined by the specific subunit composition of the receptor heteromer [18]. It has been known for some
Receptors for the tachykinin peptides substance P and neurokinin A
In the gastrointestinal tract, there are three receptors for tachykinin peptides: neurokinin-1 (NK-1), neurokinin-2 (NK-2) and neurokinin 3 (NK-3). There are at least two endogenous ligands for these receptors, substance P (SP) and neurokinin A (NKA), found in neurons of the ENS 1., 7., 8•., 39.. Immunohistochemical data indicate that NK-1 and NK-3, but not NK-2 receptors, are localized to nerve cell bodies in the myenteric or submucosal plexus 40., 41.. Therefore, one or both of these
Other synaptic transmitters
Enteric neurons contain and release many other substances that are potential neurotransmitters in enteric ganglia. However, synaptic responses mediated by these other substances have not been identified, largely due to the lack of adequate pharmacological tools. Substances in this category include vasoactive intestinal peptide, somatostatin, calcitonin gene related peptide, neuropeptide Y, pituitary adenylate cyclase activating peptide and the enkephalins. The role of these and other substances
Conclusion
There are many potential chemical messenger substances contained in, and released from, neurons in the ENS, and enteric neurons express receptors for most of these substances. However, the contribution of most of these chemical messengers and their receptors to synaptic transmission has not been established. This review has focused on several known fast and slow excitatory synaptic transmitters and the contribution of these neurotransmitters to specific motor pathways in the intestine.
Update
A recent study [51] examined the 5-HT3 receptor subunits expressed by myenteric neurons in the small intestine of wild-type and serotonin transporter (SERT) knockout (KO) mice. This is the first study to identify the 5-HT3 receptor subunits expressed by enteric neurons. These investigators showed that myenteric neurons express mRNA coding for the 5-HT3A and 5-HT3B subunits, suggesting that the enteric neuronal 5-HT3 receptor is heteromeric. These investigators also found that expression of mRNA
Acknowledgements
Work in the author's laboratory was supported by grant numbers NS33289 and DK57039 from the National Institutes of Health.
References and recommended reading
Papers of particular interest, published within the annual period of review, have been highlighted as:
• of special interest
•• of outstanding interest
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