Abstract
Amino acids applied to the mucosa evoke inhibitory reflexes in guinea-pig jejunum, but the receptors involved in sensory transduction are still unclear. One promising candidate is the extracellular calcium sensing receptor (CaSR), which is expressed by mucosal enteroendocrine cells and is preferentially activated by aromatic L-amino acids. We tested this by applying various amino acids to the mucosa and recording the resulting inhibitory junction potentials (IJPs) in nearby circular smooth muscle via intracellular recording. The CaSR is stereospecific and L-Phenylalanine evoked a significantly larger response than D-Phenylalanine when both were applied to the same site. The same pattern was seen with L- and D-Tryptophan, another aromatic amino acid. The CaSR is preferentially activated by aromatic amino acids and responses to L-Leucine and L-Lysine were significantly lower than those to L-Phenylalanine applied to the same site. Responses to L-Phenylalanine were dose-dependently suppressed by blockade of the CaSR with NPS2143, a CaSR antagonist, and mimicked by mucosal application of cinacalcet, a CaSR agonist. Responses to cinacalcet had similar pharmacology to that of responses to L-Phenylalanine, in that each requires both P2 purinoreceptors and 5-HT receptors. L-Glutamate evoked IJPs similar to those produced by L-Phenylalanine and these were depressed by blockade of P2 receptors and 5-HT3 plus 5-HT4 receptors, but NPS2143 was ineffective. The AMPA receptor antagonists DNQX (10 μM) and CNQX (10 μM) reduced IJPs evoked by L-Glutamate by 88 and 79% respectively, but neither BAY367260 (mGluR5 antagonist) nor 2APV (NMDA antagonist) affected IJPs evoked by L-Glutamate. We conclude that local inhibitory reflexes evoked by aromatic L-amino acids in guinea pig jejunum involve activation of CaSRs which triggers release of ATP and 5-HT from the mucosa. L-Glutamate also evokes inhibitory reflexes, via a pathway that does not involve CaSRs. It is likely there are multiple receptors acting as sensory transducers for different luminal amino acids.
Highlights
The primary functions of the gastrointestinal tract are controlled by the enteric nervous system (ENS) but the mechanisms by which luminal nutrients are coupled to appropriate changes in intestinal motility remain poorly understood
Responses consisted of inhibitory junction potentials (IJPs), which were sometimes followed by a slow depolarization as reported previously (Gwynne and Bornstein, 2007)
The results of this study demonstrate involvement of extracellular calcium sensing receptor (CaSR) in sensing aromatic L-amino acids in guinea pig jejunal mucosa leading to the activation of local inhibitory reflexes in the circular muscle
Summary
The primary functions of the gastrointestinal tract are controlled by the enteric nervous system (ENS) but the mechanisms by which luminal nutrients are coupled to appropriate changes in intestinal motility remain poorly understood. There is strong evidence to suggest that at least one way this detection process or “chemosensation” occurs is via activation of specialized receptors for nutrients on mucosal enteroendocrine (EE cells) or other types of epithelial cells which release their contents (e.g., 5-HT, CCK) basally to excite intrinsic (and extrinsic) sensory nerve terminals lying in the lamina propria (Sternini et al, 2008; Wellendorph et al, 2009; Hong et al, 2012) Activation of these neurons in turn excites enteric neural circuits responsible for generating motor patterns. The T1R1/T1R3 heterodimer which senses the distinct taste of “umami” elicited by L-Glutamate (L-Glu), and the metabotropic glutamate receptor mGluR4, have both been shown to function as broad sensors of L-amino-acids (Nelson et al, 2002; Chaudhari et al, 2009)
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
