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Role of CRF 2 Receptors in Colonic Ion Secretion in Response to Stress‐related Peptides
Author(s) -
Liu Sumei,
Karo Aaron
Publication year - 2021
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2021.35.s1.01702
Subject(s) - urocortin , medicine , receptor , endocrinology , agonist , ussing chamber , secretion , antagonist , chemistry , corticotropin releasing hormone , receptor antagonist , irritable bowel syndrome
Background and Aims Stress increases intestinal secretion and exacerbates symptoms of irritable bowel syndrome (IBS). Peripherally‐derived corticotropin‐releasing factor (CRF) is known to mediate stress‐induced intestinal secretion, presumably by activation of CRF 1 receptors in the gut. The present study aimed to ascertain the role of CRF 2 activation in intestinal secretion by three other members of CRF peptide family, urocortin (UCN) 1‐3, in wild‐type (WT) and CRF 2 knockout ( Crhr2 ‐/‐ ) mice. Methods Mucosal/submucosal preparations from proximal colon of WT and Crhr2 ‐/‐ mice of adult male mice were mounted in Ussing chambers for measurement of short‐circuit current ( I sc ) as an indicator of ion secretion. Results The colonic mucosa/submucosa preparations were exposed to different concentrations of UCN1, 2, or 3 (30 nM, 100 nM, 300 nM, and 1 mM) on the basolateral side. All three UCNs evoked increases in colonic I SC (Δ I SC ) in a dose‐dependent manner. The EC 50 s were 392.64nM for UCN1, 103.28nM for UCN2, and 231.21nM for UCN3. Application of CRF or stressin1 (a selective CRF 1 receptor agonist) (30nM – 1mM) also caused increases in I SC with an EC 50 of 597.04nM or 588.84nM, respectively. The potency order was therefore UCN2 > UCN3 > UCN1 > stressin1 » CRF. At each concentration tested, UCN3 produced significantly greater Δ I SC responses than that caused by stressin1, CRF, UCN1, or UCN2. Involvement of the CRF receptor subtypes in UCN1‐3 evoked Δ I SC responses was investigated with the selective CRF 1 receptor antagonist NBI27914 and the selective CRF 2 receptor antagonist antisauvagine‐30. Both NBI27914 and antisauvagine‐30 significantly suppressed UCN1 (300nM)‐induced Δ I SC responses ( p < 0.05). The Δ I SC responses evoked by UCN2 (100nM) and UCN3 (100nM) were significantly suppressed by antisauvagine‐30 ( p < 0.05 and p < 0.0001, respectively), but were not influenced by NBI27914 ( p > 0.05). In the Crhr2 ‐/‐ mice, UCN2 (1mM) failed to evoke any Δ I SC compared with WT controls ( p < 0.01). UCN3 (1mM)‐evoked Δ I SC responses were significantly decreased by 57.21% in the Crhr2 ‐/‐ mice compared with WT mice ( p < 0.05). In contrast, stressin1 (1mM)‐evoked Δ I SC response did not differ between WT and Crhr2 ‐/‐ mice ( p > 0.05). Conclusions UCN1‐3 all caused an increase of colonic ion secretion, which mimicked the effects of stress and CRF. UCN1‐induced increase of colonic ion secretion was mediated by both CRF 1 and CRF 2 , whereas UCN2 and UCN3‐induced increase of colonic ion secretion was mediated only by CRF 2 . Since UCN2 and UCN3 have greater potency and efficacy on colonic ion secretion compared with UCN1, CRF, and stressin1, it is logical to conclude that CRF 2 receptors played a predominant role in the pro‐secretory effects of UCNs.

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