GPCR-Mediated Integration of Enteroendocrine Signaling Exemplified by an L Cell

Intestinal enteroendocrine cells (IECs) secrete gut peptides in response to both nutrients and non-nutrients. Glucose and amino acids both stimulate gut peptide secretion. The gut hormone gluco-insulinotropic peptide (GIP) is secreted from IEC K-cells and the gut hormones glucagon-like peptide-1 (GLP-1) and peptide tyrosine tyrosine (PYY) are secreted from IEC L-cells. Both IECs are distributed throughout the gastrointestinal tract and are targets for anti-diabetic therapies since GIP and GLP-1 directly stimulate insulin secretion. The secretion of these peptides has been extensively investigated and the current model of IEC sensing involves both raised intracellular Ca2+ and cAMP.A number of GPCRs have been identified on GLP-1- secreting L cells. They are activated by hormones and neurotransmitters released from other IECs and the enteric nervous system and they recruit through the same pathways as the nutrient-sensing GPCRs (see gpcr_mediated_nutrient_sensing_pathway).IECs of the intestine signaling pathways targeted by their secreted products can be paracrine, hormonal, or neuronal. Unlike the faster neurotransmission pathways utilized in the voluntary nervous system, signaling in these autonomic nerves is primarily GPCR based, employing acetylcholine and noradrenaline as well as a range of peptide neurotransmitters including vasoactive intestinal peptide (VIP), calcitonin gene-related peptide (CGRP), pituitary adenlyate cyclase-activating protein (PACAP), galanin, and the bombesin-related peptides, neuromedin B (NMB) and gastrin-releasing peptide (GRP).The G-proteins are encoded by at least 16 different alpha subunit genes, 4 beta subunit genes, and 11 gamma subunit genes. They are primarily classified based upon their alpha subunits and the corresponding downstream signaling pathways they recruit and can be grouped into four families: G alpha s, G alpha i, G alpha q, and G alpha 12/13. G alpha s stimulates adenylate cylase (AC) and consequently elevates the concentration of cyclic adenosine monophosphate (cAMP) within a cell. G alpha i inhibits AC and decreases intracellular cAMP. G alpha q stimulates phospholipase C (PLC), leading to the generation of diacylglycerol (DAG) and inositol triphosphate (IP3), which respectively activate protein kinase (PK) C and trigger Ca2+ release from intracellular stores. This modulates the release of the L cell peptides GLP-1, GLP-2, oxyntomodulin, and PYY, which in turn activate GPCRs shown to be expressed on afferent nerves.