Functional domains essential for Gs activity in prostaglandin EP2 and EP3 receptors

Sugimoto, Yukihiko; Nakato, Toshiyuki; Kita, Ayumi; Hatae, Noriyuki; Tabata, Hiroyuki; Tanaka, Satoshi; Ichikawa, Atsushi

doi:10.1016/j.lfs.2003.09.002

Cited by 14 publications

(9 citation statements)

References 18 publications

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“…Likewise, the extracellular sequence of the EP 2 receptor is a critical determinant of its structure and function (Stillman et al ., 1999). Similarly, a cluster of hydrophobic aromatic amino acids in the second intracellular loop of EP 2 but not EP 3 isoform β is absolutely essential for activation of G α s subunit (Sugimoto et al ., 2003, 2004). Pharmacologically, EP receptors exhibit differences in binding to various ligands (Table 1) and surprisingly, the affinity of these receptors to its principal ligand, PGE 2 , greatly varies between receptor subtypes (Tables 2 and 3).…”

Section: Diversity In Ep Receptor Signalling and Functionsmentioning

confidence: 99%

Prostaglandin E₂ receptor distribution and function in the gastrointestinal tract

Dey

Lejeune

Chadee

2006

British J Pharmacology

220

195

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Prostaglandin E 2 (PGE 2 ) is one of the most important biologically active prostanoids found throughout the gastrointestinal tract. Despite the fact that PGE 2 regulates many physiological functions of the gut including mucosal protection, gastrointestinal secretion and motility, it is implicated in the pathophysiology of inflammatory bowel diseases (IBD) and colorectal neoplasia. The varied biological functions exerted by PGE 2 are through the pharmacologically distinct, G-protein coupled plasma membrane receptors termed EP receptors. Disruptions of various prostanoid receptor genes have helped in unravelling the physiological functions of these receptors. To date, all four subtypes of EP receptors have been individually knocked out in mice and various phenotypes have been reported for each subtype. Similarly, in vitro and in vivo studies using EP receptor agonists and antagonists have helped in uncoupling the diverse functions of PGE 2 signalling involving distinct EP receptors in the gut. In this review, we will summarize and conceptualize the salient features of EP receptor subtypes, their regional functions in the gut and how expressions of EP receptors are altered during disease states.

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Section: Diversity In Ep Receptor Signalling and Functionsmentioning

confidence: 99%

Prostaglandin E₂ receptor distribution and function in the gastrointestinal tract

Dey

Lejeune

Chadee

2006

British J Pharmacology

220

195

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“…Although the mechanisms underlying PGE 2 -induced currents via acting EP3 receptor are not clear, we reason that PGE 2 evokes currents via activating the ion channels including TRPV1. PGE 2 receptors comprise of four subtypes (EP1-EP4), among which EP3 receptors uniquely couple to Gi protein [59,60].…”

Section: Discussionmentioning

confidence: 99%

Interaction of TRPV1 and EP3 Receptor in Cough and Bronchopulmonary C-Neural Activities

Gao¹,

Zhuang²,

Zhao³

et al. 2020

Preprint

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Prostaglandin E2 (PGE2)-induced coughs in vivo and vagal nerve depolarization in vitro are inhibited by systemic and local administration of TRPV1 (JNJ 17203212) and prostaglandin EP3 receptor antagonists (L-798106) respectively. These results indicate an interaction of TRPV1 and EP3 receptor in cough responses to PGE2 likely through the vagal sensory nerve. This study aimed to determine whether 1) inhalation of aerosolized JNJ 17203212 and L-798106 affected cough responses to citric acid (CA to mainly stimulate TRPV1) and PGE2; 2) TRPV1 and EP3 receptor morphologically co-expressed and electrophysiologically functioned in the individual of vagal pulmonary C-neurons (cell bodies of bronchopulmonary C-fibers in the nodose/jugular ganglia); and 3) the interaction of the two receptors occurred in these neurons. To this end, aerosolized CA or PGE2 was inhaled by unanesthetized guinea pigs pretreated without or with JNJ 17203212 or L-798106 given in aerosol. Immunofluorescence was applied to identify the expression of the two receptors in vagal pulmonary C-neurons (retrogradely traced by DiI). Whole-cell patch clamp approach was used to detect capsaicin (CAP)- and PGE2-induced currents in the same neurons and determine the effects of the TRPV1 and EP3 receptor antagonists on the currents. We found that PGE2-evoked cough was attenuated by JNJ 17203212 or L-798106 and CA-evoked cough greatly suppressed only by JNJ 17203212. EP3-labeled neurons always co-expressed TRPV1 with a cell size < 20 µm and occupied 1/4 of vagal pulmonary C-neurons. Both CAP- and PGE2-induced currents could be recorded in the individuals of some vagal pulmonary C-neurons. The former was largely inhibited only by JNJ 17203212, while the latter was suppressed by JNJ 17203212 or L-798106. The similarity of the interaction in cough and vagal pulmonary C-neural activity suggests that a subgroup of vagal pulmonary C-neurons co-expressing TRPV1 and EP3 receptor is, at least in part, responsible for the interaction of the two receptors in the cough response to PGE2.

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“…In the rat, there are three splice-variants of the EP3 gene that differ at the c-terminal region, an area important for G-protein coupling. As such, EP3 was originally identified as coupled to G i , which can inhibit the production of cAMP by adenylyl cyclase, but later studies also described G s and G 13 coupling (Aoki et al, 1999; Sugimoto et al, 2003). The G 13 coupling can in turn activate Rho in the family of small GTPases (Katoh et al, 1998).…”

Section: Discussionmentioning

confidence: 99%

Identification of prostaglandin E2 receptors mediating perinatal masculinization of adult sex behavior and neuroanatomical correlates

Wright

Burks

McCarthy

2008

Developmental Neurobiology

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Prostaglandin E2 (PGE2) mediates the organization of male rat sexual behavior and medial preoptic area (MPOA) neuroanatomy during a sensitive perinatal window. PGE2 is up-regulated in response to estradiol, and initiates a two-fold increase in dendritic spines densities on neurons. All the four receptors for PGE2 and EP1-4 are present in developing POA, a critical region controlling male sexual behavior. Previous studies explored that EP receptors are involved in PGE2-induction of neonatal levels of spinophilin protein, a surrogate marker for dendritic spine formation, but did not assess behavioral masculinization. Here, we used two approaches, suppression of EP receptor expression with antisense oligonucleotides and activation of EP receptors with selective agonists, to test which receptors are necessary and sufficient, respectively, for the effects of PGE2 on behavior and neuronal morphology. In female rats, neonatal treatment with antisense oligonucleotides against EP2 or EP4 but not EP1 or EP3 completely prevented the expression of adult behavior organized by PGE2 exposure. The effects of ONO-DI-004, ONO-AE-259-01, ONO-AE-248, and ONO-AE1-329 (EP1-4 agonists respectively) were equivalent to PGE2 treatment, which suggests activating any EP receptor neonatally suffices in masculinizing sex behavior. When given alone, not all EP agonists increased neonatal POA spinophilin levels; yet giving each agonist neonatally increased adult levels. Moreover, adult spinophilin levels significantly correlated with two measures of male sexual behavior. The body of evidence suggests that EP2 and EP4 are both necessary and sufficient for PGE2-induced masculinization of sex behavior, whereas EP1 and EP3 provide redundant roles.

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Functional domains essential for Gs activity in prostaglandin EP2 and EP3 receptors

Cited by 14 publications

References 18 publications

Prostaglandin E₂ receptor distribution and function in the gastrointestinal tract

Prostaglandin E₂ receptor distribution and function in the gastrointestinal tract

Interaction of TRPV1 and EP3 Receptor in Cough and Bronchopulmonary C-Neural Activities

Identification of prostaglandin E2 receptors mediating perinatal masculinization of adult sex behavior and neuroanatomical correlates

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Functional domains essential for Gs activity in prostaglandin EP2 and EP3 receptors

Cited by 14 publications

References 18 publications

Prostaglandin E2 receptor distribution and function in the gastrointestinal tract

Prostaglandin E2 receptor distribution and function in the gastrointestinal tract

Interaction of TRPV1 and EP3 Receptor in Cough and Bronchopulmonary C-Neural Activities

Identification of prostaglandin E2 receptors mediating perinatal masculinization of adult sex behavior and neuroanatomical correlates

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Prostaglandin E₂ receptor distribution and function in the gastrointestinal tract

Prostaglandin E₂ receptor distribution and function in the gastrointestinal tract