GPCR-Mediated Nutrient Sensing in Enteroendocrine Cells

Specialized epithelial cells, enteroendocrine cells (EEC), form the basis of the largest endocrine system in the body. They secrete multiple regulatory molecules which control physiological and homeostatic functions, particularly postprandial secretion and motility. Chemosensation in the gut is considered to occur in EECs and tuft cells, more reminiscent of the relatively short-lived taste-responsive cells on the mammalian tongue.G-protein-coupled receptors (GPCRs) responsive to a range of nutrients and other food components have been identified, and many are localized to intestinal chemosensory cells, eliciting hormonal and neuronal signaling to the brain and periphery.Extracellular ligand-binding to GPCRs induces conformational changes that alter a receptor's interface with cytosolic effectors, primarily the membrane-bound heterotrimeric guanine nucleotide-binding G-proteins, alpha, beta, and gamma, which, once activated, dissociate and stimulate their respective effector pathways. 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. The consequent elevation of cytoplasmic Ca2+ activates the Ca2+-sensitive transient receptor potential channel M5 (TRPM5) triggering membrane depolarization and activation of voltage-gated Ca2+ channels thereby triggering the influx of Ca2+ Members of the T1R family of taste receptors function as molecular complexes. For instance, the heterodimeric T1R2/T1R3 sweet taste receptor binds sweet stimuli, whereas T1R1/T1R3 recognizes amino acids. TRPM5, has been specifically linked to bitter and sweet signal transduction. TRPM5 has been identified as a voltage-modulated, Ca2+-activated, monovalent cation channel that activates and deactivates rapidly, thereby inducing transient membrane depolarization.There are four principal GPCRs identified to respond to free fatty acids, FFAR1-FFAR3 and GPR120 FFAR1 (GPR40) and GPR120 respond to medium-chain fatty acids to LCFA and are predominantly G alpha q coupled, whereas FFAR2 and FFAR3 are stimulated by SCFA, produced in the distal gut by fermentation of dietary fiber.Among the GPCRs, the strongest candidate amino acid sensor in EECs is currently CaSR. This receptor was originally identified as the Ca2+ sensor in the parathyroid gland, but is also found throughout the GI tract in a number of cell types where it has been linked to numerous physiological responses, including motility.Both GPCR-dependent and -independent pathways have been implicated in peptide and amino acid detection. Some amino acids, like glutamine, have been shown to depolarize EECs as a direct consequence of their electrogenic uptake via sodium-coupled transporters, resulting in voltage-gated Ca2+ entry and Ca2+- dependent stimulation of secretion and in turn the release of gastrointestinal (GI) peptides.