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Pharmacology and physiology of gastrointestinal enteroendocrine cells.

Mace OJ, Tehan B, Marshall F - Pharmacol Res Perspect (2015)

Bottom Line: Typically obese patients exhibit ∼30% weight loss and greater than 80% of obese diabetics show remission of diabetes.Targeting combinations of enteroendocrine signaling pathways that work synergistically may manifest with significant, differentiated EEC secretory efficacy.Together with the potential to bias enteroendocrine GPCR signaling and/or to activate multiple divergent signaling pathways highlights the considerable range of therapeutic possibilities available.

View Article: PubMed Central - PubMed

Affiliation: Heptares Therapeutics Ltd BioPark, Broadwater Road, Welwyn Garden City, AL7 3AX, United Kingdom.

ABSTRACT
Gastrointestinal (GI) polypeptides are secreted from enteroendocrine cells (EECs). Recent technical advances and the identification of endogenous and synthetic ligands have enabled exploration of the pharmacology and physiology of EECs. Enteroendocrine signaling pathways stimulating hormone secretion involve multiple nutrient transporters and G protein-coupled receptors (GPCRs), which are activated simultaneously under prevailing nutrient conditions in the intestine following a meal. The majority of studies investigate hormone secretion from EECs in response to single ligands and although the mechanisms behind how individual signaling pathways generate a hormonal output have been well characterized, our understanding of how these signaling pathways converge to generate a single hormone secretory response is still in its infancy. However, a picture is beginning to emerge of how nutrients and full, partial, or allosteric GPCR ligands differentially regulate the enteroendocrine system and its interaction with the enteric and central nervous system. So far, activation of multiple pathways underlies drug discovery efforts to harness the therapeutic potential of the enteroendocrine system to mimic the phenotypic changes observed in patients who have undergone Roux-en-Y gastric surgery. Typically obese patients exhibit ∼30% weight loss and greater than 80% of obese diabetics show remission of diabetes. Targeting combinations of enteroendocrine signaling pathways that work synergistically may manifest with significant, differentiated EEC secretory efficacy. Furthermore, allosteric modulators with their increased selectivity, self-limiting activity, and structural novelty may translate into more promising enteroendocrine drugs. Together with the potential to bias enteroendocrine GPCR signaling and/or to activate multiple divergent signaling pathways highlights the considerable range of therapeutic possibilities available. Here, we review the pharmacology and physiology of the EEC system.

No MeSH data available.


Related in: MedlinePlus

Sensing by the enteroendocrine system. Digestion products enter the small intestine and stimulate enteroendocrine cells (EECs) to secrete hormones which modulate gastrointestinal (GI) secretion, insulin secretion, gastric and GI motility, and satiety. Open type EECs have processes that extend to reach into the lumen to detect nutrients. Glucose, amino acids, and peptides are sensed by EECs via nutrient transporters (A). Nutrient transport depolarizes the plasma membrane (PM). Nutrient uptake signaling converges on voltage-gated Ca2+ channels (VGCCs). Plasma membrane depolarisation (ΔΨ) opens VGCCs allowing entry of extracellular Ca2+ to raise intracellular Ca2+ levels [Ca2+]I and stimulate the secretion of hormones from EECs. Glucose is sensed by electrogenic Na+-coupled uptake by sodium-coupled glucose transporter (SGLT1) to trigger membrane depolarization and the entry of extracellular Ca2+ via VGCCs. Intracellular metabolism of glucose or fructose via glucokinase, and closure of ATP-sensitive K+ channels also causes membrane depolarization and opening of VGCCs. Electrogenic uptake of certain amino acids via H+ or Na+ coupled amino acid transporters or peptides via the H+ coupled peptide transporter-1 (PepT1) can also trigger membrane depolarization and hormone secretion. Nutrients are also sensed by GPCRs (B). GPCR-mediated nutrient sensing in EECs stimulate the release of hormones via coupling to Gαs and Gαi that promote or inhibit adenylate cyclase activity, respectively, altering intracellular cAMP levels [cAMP]I. Gαq/11-coupled GPCRs stimulate phospholipase C activity to breakdown PIP2 into IP3 and DAG. Intracellular stores release Ca2+ in response to activation of IP3 receptors. Protein kinase C is activated by Ca2+ and DAG. Gαgustducin couples to TRPM5 via phospholipase Cβ2 and Ca2+ to cause membrane depolarization and open VGCCs. For example, fatty acids activate FFAR1 – 4 which mobilize Ca2+ while CB1 inhibits cAMP production. Products of triacylglycerol digestion, including oleoylethanolamide and monoacylglycerols, activate GPR119 to increase cAMP levels. Amino acids and oligopeptides also activate the CasR to trigger hormone secretion. Nutrient transporters are shown to highlight that these signaling pathways also operate in the presence of nutrient. Enteroendocrine signaling is integrated through GPCR signaling cascades. Hormones secreted from EECs may mediate effects locally or systemically. For example, hormones may enter the systemic circulation and the hepatic portal vein to activate receptors in other tissues via endocrine pathways (C). These hormones may activate receptors on enterocytes for example, PYY may activate NPY1R which increases cAMP levels and inhibits Cl− secretion or VIP may activate VPAC to decrease cAMP and stimulate Cl− secretion (D) or EECs in the vicinity, for example, CCK may activate CCK1R, GIP may activate GIPR, and Sst may activate SSTR5 (E). Hormones may activate GPCRs on vagal afferent neurones, for example, PYY may activate NPY1R, CCK may activate CCK1R, and GLP-1 or 2 may activate GLP1R or GLP2R, respectively (F). The enteric nervous system (ENS) also modulates EEC activity through the release of hormones and neurotransmitters including Ach (M2R), GRP/NMB (BBS2), PACAP (VPAC1R), galanin (GAL1), or α-MSH (MC4R) (G). The ENS can also detect absorbed nutrients through GPCRs including FFAR3 (H).
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fig01: Sensing by the enteroendocrine system. Digestion products enter the small intestine and stimulate enteroendocrine cells (EECs) to secrete hormones which modulate gastrointestinal (GI) secretion, insulin secretion, gastric and GI motility, and satiety. Open type EECs have processes that extend to reach into the lumen to detect nutrients. Glucose, amino acids, and peptides are sensed by EECs via nutrient transporters (A). Nutrient transport depolarizes the plasma membrane (PM). Nutrient uptake signaling converges on voltage-gated Ca2+ channels (VGCCs). Plasma membrane depolarisation (ΔΨ) opens VGCCs allowing entry of extracellular Ca2+ to raise intracellular Ca2+ levels [Ca2+]I and stimulate the secretion of hormones from EECs. Glucose is sensed by electrogenic Na+-coupled uptake by sodium-coupled glucose transporter (SGLT1) to trigger membrane depolarization and the entry of extracellular Ca2+ via VGCCs. Intracellular metabolism of glucose or fructose via glucokinase, and closure of ATP-sensitive K+ channels also causes membrane depolarization and opening of VGCCs. Electrogenic uptake of certain amino acids via H+ or Na+ coupled amino acid transporters or peptides via the H+ coupled peptide transporter-1 (PepT1) can also trigger membrane depolarization and hormone secretion. Nutrients are also sensed by GPCRs (B). GPCR-mediated nutrient sensing in EECs stimulate the release of hormones via coupling to Gαs and Gαi that promote or inhibit adenylate cyclase activity, respectively, altering intracellular cAMP levels [cAMP]I. Gαq/11-coupled GPCRs stimulate phospholipase C activity to breakdown PIP2 into IP3 and DAG. Intracellular stores release Ca2+ in response to activation of IP3 receptors. Protein kinase C is activated by Ca2+ and DAG. Gαgustducin couples to TRPM5 via phospholipase Cβ2 and Ca2+ to cause membrane depolarization and open VGCCs. For example, fatty acids activate FFAR1 – 4 which mobilize Ca2+ while CB1 inhibits cAMP production. Products of triacylglycerol digestion, including oleoylethanolamide and monoacylglycerols, activate GPR119 to increase cAMP levels. Amino acids and oligopeptides also activate the CasR to trigger hormone secretion. Nutrient transporters are shown to highlight that these signaling pathways also operate in the presence of nutrient. Enteroendocrine signaling is integrated through GPCR signaling cascades. Hormones secreted from EECs may mediate effects locally or systemically. For example, hormones may enter the systemic circulation and the hepatic portal vein to activate receptors in other tissues via endocrine pathways (C). These hormones may activate receptors on enterocytes for example, PYY may activate NPY1R which increases cAMP levels and inhibits Cl− secretion or VIP may activate VPAC to decrease cAMP and stimulate Cl− secretion (D) or EECs in the vicinity, for example, CCK may activate CCK1R, GIP may activate GIPR, and Sst may activate SSTR5 (E). Hormones may activate GPCRs on vagal afferent neurones, for example, PYY may activate NPY1R, CCK may activate CCK1R, and GLP-1 or 2 may activate GLP1R or GLP2R, respectively (F). The enteric nervous system (ENS) also modulates EEC activity through the release of hormones and neurotransmitters including Ach (M2R), GRP/NMB (BBS2), PACAP (VPAC1R), galanin (GAL1), or α-MSH (MC4R) (G). The ENS can also detect absorbed nutrients through GPCRs including FFAR3 (H).

Mentions: Nutrient uptake across the apical brush border membrane elicits membrane depolarization (Fig.1A). Depolarization of the plasma membrane (PM) regulates the opening of voltage-gated Ca2+ channels (VGCCs), including l-type Ca2+ channels, which control EEC secretory activity (Fig.1). The traditional dogma has been that functional l-type Ca2+ channels are not expressed in intestine, however, this has been challenged in more recent years (Morgan et al. 2003, 2007; Mace et al. 2007; Kellett et al. 2008; Kellett 2011). During the prandial period, the PM of the intestine is hyperpolarized; VGCCs are closed, ATP-sensitive K+ channels are open, and EECs are silent. The PM becomes depolarized as a result of electrogenic or facilitative nutrient transport following nutrient ingestion. Glucose transport via the sodium-coupled glucose transporter (SGLT1), peptide transport via the proton-coupled peptide transporter (PepT1), or amino acid transport via their electrogenic transporters (e.g., glutamine or asparagine) depolarize the PM. Numerous studies have shown through both pharmacological and genetic methods that SGLT1 transport plays a vital role in GIP, GLP-1, and PYY secretion (Sykes et al. 1980; Shima et al. 1990; Ritzel et al. 1997; Mace et al. 2012). There is no doubt that the stimulation of GIP and GLP-1 by luminal glucose is diminished by pharmacological inhibitors of electrogenic glucose uptake (Sykes et al. 1980; Ritzel et al. 1997; Mace et al. 2012). Facilitative transport can also depolarize the PM by virtue of intracellular sugar metabolism, altering the ADP:ATP ratio and closure of ATP-sensitive K+ channels. The protein components required for the stimulation of hormone secretion from EECs by intracellular metabolism, including glucokinase and ATP-sensitive K+ channels, are expressed by L and K cells, and studies using GLUTag cells indicate that intracellular sugar metabolism may stimulate secretory activity (Parker et al. 2012a); the facilitative glucose (GLUT2) and fructose (GLUT5) transporters are also expressed. Additional physiological evidence, in addition to that showing oral fructose is able to stimulate GLP-1 secretion in mice, rats, and humans (Kong et al. 1999; Kuhre et al. 2014), for a role of facilitative transport in hormone secretion derives from genetic studies in which the GLP-1 secretory response to oral glucose in GLUT2−/− mice was diminished (Cani et al. 2007) and from isolated perfused rat intestine preparations where fructose stimulated GLP-1 secretion (Ritzel et al. 1997) and GIP, GLP-1, and PYY secretion could be blocked using pharmacological inhibitors (Mace et al. 2012). More recently, apical glucose transport has also been demonstrated to control the secretion of the neurohormone, neurotensin, from enteroendocrine N-cells (Table1) using preparations of isolated rat small intestine (Kuhre et al. 2015). Pharmacological inhibition of SGLT1 or GLUT2 blocked neurotensin release in response to luminal glucose; the facilitative glucose transporter involved a molecular pathway causing closure of ATP-sensitive K+ channels (Kuhre et al. 2015).


Pharmacology and physiology of gastrointestinal enteroendocrine cells.

Mace OJ, Tehan B, Marshall F - Pharmacol Res Perspect (2015)

Sensing by the enteroendocrine system. Digestion products enter the small intestine and stimulate enteroendocrine cells (EECs) to secrete hormones which modulate gastrointestinal (GI) secretion, insulin secretion, gastric and GI motility, and satiety. Open type EECs have processes that extend to reach into the lumen to detect nutrients. Glucose, amino acids, and peptides are sensed by EECs via nutrient transporters (A). Nutrient transport depolarizes the plasma membrane (PM). Nutrient uptake signaling converges on voltage-gated Ca2+ channels (VGCCs). Plasma membrane depolarisation (ΔΨ) opens VGCCs allowing entry of extracellular Ca2+ to raise intracellular Ca2+ levels [Ca2+]I and stimulate the secretion of hormones from EECs. Glucose is sensed by electrogenic Na+-coupled uptake by sodium-coupled glucose transporter (SGLT1) to trigger membrane depolarization and the entry of extracellular Ca2+ via VGCCs. Intracellular metabolism of glucose or fructose via glucokinase, and closure of ATP-sensitive K+ channels also causes membrane depolarization and opening of VGCCs. Electrogenic uptake of certain amino acids via H+ or Na+ coupled amino acid transporters or peptides via the H+ coupled peptide transporter-1 (PepT1) can also trigger membrane depolarization and hormone secretion. Nutrients are also sensed by GPCRs (B). GPCR-mediated nutrient sensing in EECs stimulate the release of hormones via coupling to Gαs and Gαi that promote or inhibit adenylate cyclase activity, respectively, altering intracellular cAMP levels [cAMP]I. Gαq/11-coupled GPCRs stimulate phospholipase C activity to breakdown PIP2 into IP3 and DAG. Intracellular stores release Ca2+ in response to activation of IP3 receptors. Protein kinase C is activated by Ca2+ and DAG. Gαgustducin couples to TRPM5 via phospholipase Cβ2 and Ca2+ to cause membrane depolarization and open VGCCs. For example, fatty acids activate FFAR1 – 4 which mobilize Ca2+ while CB1 inhibits cAMP production. Products of triacylglycerol digestion, including oleoylethanolamide and monoacylglycerols, activate GPR119 to increase cAMP levels. Amino acids and oligopeptides also activate the CasR to trigger hormone secretion. Nutrient transporters are shown to highlight that these signaling pathways also operate in the presence of nutrient. Enteroendocrine signaling is integrated through GPCR signaling cascades. Hormones secreted from EECs may mediate effects locally or systemically. For example, hormones may enter the systemic circulation and the hepatic portal vein to activate receptors in other tissues via endocrine pathways (C). These hormones may activate receptors on enterocytes for example, PYY may activate NPY1R which increases cAMP levels and inhibits Cl− secretion or VIP may activate VPAC to decrease cAMP and stimulate Cl− secretion (D) or EECs in the vicinity, for example, CCK may activate CCK1R, GIP may activate GIPR, and Sst may activate SSTR5 (E). Hormones may activate GPCRs on vagal afferent neurones, for example, PYY may activate NPY1R, CCK may activate CCK1R, and GLP-1 or 2 may activate GLP1R or GLP2R, respectively (F). The enteric nervous system (ENS) also modulates EEC activity through the release of hormones and neurotransmitters including Ach (M2R), GRP/NMB (BBS2), PACAP (VPAC1R), galanin (GAL1), or α-MSH (MC4R) (G). The ENS can also detect absorbed nutrients through GPCRs including FFAR3 (H).
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Show All Figures
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fig01: Sensing by the enteroendocrine system. Digestion products enter the small intestine and stimulate enteroendocrine cells (EECs) to secrete hormones which modulate gastrointestinal (GI) secretion, insulin secretion, gastric and GI motility, and satiety. Open type EECs have processes that extend to reach into the lumen to detect nutrients. Glucose, amino acids, and peptides are sensed by EECs via nutrient transporters (A). Nutrient transport depolarizes the plasma membrane (PM). Nutrient uptake signaling converges on voltage-gated Ca2+ channels (VGCCs). Plasma membrane depolarisation (ΔΨ) opens VGCCs allowing entry of extracellular Ca2+ to raise intracellular Ca2+ levels [Ca2+]I and stimulate the secretion of hormones from EECs. Glucose is sensed by electrogenic Na+-coupled uptake by sodium-coupled glucose transporter (SGLT1) to trigger membrane depolarization and the entry of extracellular Ca2+ via VGCCs. Intracellular metabolism of glucose or fructose via glucokinase, and closure of ATP-sensitive K+ channels also causes membrane depolarization and opening of VGCCs. Electrogenic uptake of certain amino acids via H+ or Na+ coupled amino acid transporters or peptides via the H+ coupled peptide transporter-1 (PepT1) can also trigger membrane depolarization and hormone secretion. Nutrients are also sensed by GPCRs (B). GPCR-mediated nutrient sensing in EECs stimulate the release of hormones via coupling to Gαs and Gαi that promote or inhibit adenylate cyclase activity, respectively, altering intracellular cAMP levels [cAMP]I. Gαq/11-coupled GPCRs stimulate phospholipase C activity to breakdown PIP2 into IP3 and DAG. Intracellular stores release Ca2+ in response to activation of IP3 receptors. Protein kinase C is activated by Ca2+ and DAG. Gαgustducin couples to TRPM5 via phospholipase Cβ2 and Ca2+ to cause membrane depolarization and open VGCCs. For example, fatty acids activate FFAR1 – 4 which mobilize Ca2+ while CB1 inhibits cAMP production. Products of triacylglycerol digestion, including oleoylethanolamide and monoacylglycerols, activate GPR119 to increase cAMP levels. Amino acids and oligopeptides also activate the CasR to trigger hormone secretion. Nutrient transporters are shown to highlight that these signaling pathways also operate in the presence of nutrient. Enteroendocrine signaling is integrated through GPCR signaling cascades. Hormones secreted from EECs may mediate effects locally or systemically. For example, hormones may enter the systemic circulation and the hepatic portal vein to activate receptors in other tissues via endocrine pathways (C). These hormones may activate receptors on enterocytes for example, PYY may activate NPY1R which increases cAMP levels and inhibits Cl− secretion or VIP may activate VPAC to decrease cAMP and stimulate Cl− secretion (D) or EECs in the vicinity, for example, CCK may activate CCK1R, GIP may activate GIPR, and Sst may activate SSTR5 (E). Hormones may activate GPCRs on vagal afferent neurones, for example, PYY may activate NPY1R, CCK may activate CCK1R, and GLP-1 or 2 may activate GLP1R or GLP2R, respectively (F). The enteric nervous system (ENS) also modulates EEC activity through the release of hormones and neurotransmitters including Ach (M2R), GRP/NMB (BBS2), PACAP (VPAC1R), galanin (GAL1), or α-MSH (MC4R) (G). The ENS can also detect absorbed nutrients through GPCRs including FFAR3 (H).
Mentions: Nutrient uptake across the apical brush border membrane elicits membrane depolarization (Fig.1A). Depolarization of the plasma membrane (PM) regulates the opening of voltage-gated Ca2+ channels (VGCCs), including l-type Ca2+ channels, which control EEC secretory activity (Fig.1). The traditional dogma has been that functional l-type Ca2+ channels are not expressed in intestine, however, this has been challenged in more recent years (Morgan et al. 2003, 2007; Mace et al. 2007; Kellett et al. 2008; Kellett 2011). During the prandial period, the PM of the intestine is hyperpolarized; VGCCs are closed, ATP-sensitive K+ channels are open, and EECs are silent. The PM becomes depolarized as a result of electrogenic or facilitative nutrient transport following nutrient ingestion. Glucose transport via the sodium-coupled glucose transporter (SGLT1), peptide transport via the proton-coupled peptide transporter (PepT1), or amino acid transport via their electrogenic transporters (e.g., glutamine or asparagine) depolarize the PM. Numerous studies have shown through both pharmacological and genetic methods that SGLT1 transport plays a vital role in GIP, GLP-1, and PYY secretion (Sykes et al. 1980; Shima et al. 1990; Ritzel et al. 1997; Mace et al. 2012). There is no doubt that the stimulation of GIP and GLP-1 by luminal glucose is diminished by pharmacological inhibitors of electrogenic glucose uptake (Sykes et al. 1980; Ritzel et al. 1997; Mace et al. 2012). Facilitative transport can also depolarize the PM by virtue of intracellular sugar metabolism, altering the ADP:ATP ratio and closure of ATP-sensitive K+ channels. The protein components required for the stimulation of hormone secretion from EECs by intracellular metabolism, including glucokinase and ATP-sensitive K+ channels, are expressed by L and K cells, and studies using GLUTag cells indicate that intracellular sugar metabolism may stimulate secretory activity (Parker et al. 2012a); the facilitative glucose (GLUT2) and fructose (GLUT5) transporters are also expressed. Additional physiological evidence, in addition to that showing oral fructose is able to stimulate GLP-1 secretion in mice, rats, and humans (Kong et al. 1999; Kuhre et al. 2014), for a role of facilitative transport in hormone secretion derives from genetic studies in which the GLP-1 secretory response to oral glucose in GLUT2−/− mice was diminished (Cani et al. 2007) and from isolated perfused rat intestine preparations where fructose stimulated GLP-1 secretion (Ritzel et al. 1997) and GIP, GLP-1, and PYY secretion could be blocked using pharmacological inhibitors (Mace et al. 2012). More recently, apical glucose transport has also been demonstrated to control the secretion of the neurohormone, neurotensin, from enteroendocrine N-cells (Table1) using preparations of isolated rat small intestine (Kuhre et al. 2015). Pharmacological inhibition of SGLT1 or GLUT2 blocked neurotensin release in response to luminal glucose; the facilitative glucose transporter involved a molecular pathway causing closure of ATP-sensitive K+ channels (Kuhre et al. 2015).

Bottom Line: Typically obese patients exhibit ∼30% weight loss and greater than 80% of obese diabetics show remission of diabetes.Targeting combinations of enteroendocrine signaling pathways that work synergistically may manifest with significant, differentiated EEC secretory efficacy.Together with the potential to bias enteroendocrine GPCR signaling and/or to activate multiple divergent signaling pathways highlights the considerable range of therapeutic possibilities available.

View Article: PubMed Central - PubMed

Affiliation: Heptares Therapeutics Ltd BioPark, Broadwater Road, Welwyn Garden City, AL7 3AX, United Kingdom.

ABSTRACT
Gastrointestinal (GI) polypeptides are secreted from enteroendocrine cells (EECs). Recent technical advances and the identification of endogenous and synthetic ligands have enabled exploration of the pharmacology and physiology of EECs. Enteroendocrine signaling pathways stimulating hormone secretion involve multiple nutrient transporters and G protein-coupled receptors (GPCRs), which are activated simultaneously under prevailing nutrient conditions in the intestine following a meal. The majority of studies investigate hormone secretion from EECs in response to single ligands and although the mechanisms behind how individual signaling pathways generate a hormonal output have been well characterized, our understanding of how these signaling pathways converge to generate a single hormone secretory response is still in its infancy. However, a picture is beginning to emerge of how nutrients and full, partial, or allosteric GPCR ligands differentially regulate the enteroendocrine system and its interaction with the enteric and central nervous system. So far, activation of multiple pathways underlies drug discovery efforts to harness the therapeutic potential of the enteroendocrine system to mimic the phenotypic changes observed in patients who have undergone Roux-en-Y gastric surgery. Typically obese patients exhibit ∼30% weight loss and greater than 80% of obese diabetics show remission of diabetes. Targeting combinations of enteroendocrine signaling pathways that work synergistically may manifest with significant, differentiated EEC secretory efficacy. Furthermore, allosteric modulators with their increased selectivity, self-limiting activity, and structural novelty may translate into more promising enteroendocrine drugs. Together with the potential to bias enteroendocrine GPCR signaling and/or to activate multiple divergent signaling pathways highlights the considerable range of therapeutic possibilities available. Here, we review the pharmacology and physiology of the EEC system.

No MeSH data available.


Related in: MedlinePlus