Local Regulation of Anion Secretion by Pituitary Adenylate Cyclase‐activating Polypeptide in Human Colonic T84 Cells

Abstract

Pituitary adenylate cyclase-activating polypeptide (PACAP) is a novel hypothalamic peptide, which has been shown to exert various functions in a number of tissues, including exocrine and endocrine tissues. The present study investigated the role of local PACAP in the control of anion secretion by the human colonic T84 cell. Both bioactive forms of PACAP-27 and PACAP-38 gave rise to a dose-dependent increase in the short-circuit current (I(SC)). However, there was a reversal in the order of potency observed at different concentration ranges for the two bioactive forms. PACAP-27 was greater than PACAP-38 when the peptide concentrations were below 10 n m; PACAP-38 was greater than PACAP-27 in the range of 10-80 n m. The effects of both PACAP forms were restricted to the apical aspect of the T84 cell. The I(SC)responses to both PACAP-27 and PACAP-38 were suppressed respectively by the non-selective Cl(-)channel blocker, diphenylamine-dicarboxylic acid (DPC), by the Ca(2+)dependent Cl(-)channel blocker, diisothiocyanatostilbene-disulfonic acid (DIDS) and by the Ca(2+)chelator, BAPTA-AM, indicating the involvement of Ca(2+). The expression of PACAP was demonstrated and localized specifically to the perinuclear cytoplasm of the T84 cell using immunocytochemistry, indicating its epithelial origin. Thus, the present data suggest that, in addition to the well-known cAMP-dependent pathway, PACAP may play a role in regulating colonic Cl(-)secretion via a Ca(2+)-dependent pathway, perhaps through two distinct PACAP receptor subtypes. Moreover, the regulation of anion secretion by T84 cells may be mediated by locally formed PACAP in an autocrine or paracrine fashion.

Activation of VPAC1 receptors by VIP and PACAP‐27 in human bronchial epithelial cells induces CFTR‐dependent chloride secretion

“…In conclusion, we have demonstrated that human bronchial Calu‐3 epithelial cells expressed basolateral VPAC 1 receptors which interact with VIP or PACAP‐27 causing activation of CFTR‐mediated chloride secretion via a pathway in which protein kinase A and C are both involved. Our study therefore shows that as in the intestine ( Waldman et al , 1977 ; Chang & Rao, 1991; Nguyen et al , 1992 ; Leung et al , 2001 ; Izu et al , 2002 ) CFTR is an important molecular target for the physiological action of VIP and PACAP‐27 in the chloride transepithelial transport of human bronchial epithelial cells.…”

“…In digestive tissues, it is known that VIP/PACAP receptors regulate transepithelial chloride transport ( Waldman et al , 1977 ; Chang & Rao, 1991; Nguyen et al , 1992 ; Leung et al , 2001 ; Izu et al , 2002 ). Therefore, we studied the activity of chloride channels in human airway epithelial Calu‐3 cells in the presence of VIP or PACAP‐27.…”

“…In the digestive tract, VIP is one of the principal physiological regulator of water and electrolytes secretion, especially in the intestine ( Waldman et al , 1977 ; Chang & Rao, 1991; Nguyen et al , 1992 ; Leung et al , 2001 ; Izu et al , 2002 ) and pancreas ( Ito et al , 1998 ). One plasma membrane protein appears to orchestrate these regulated secretory processes: the cystic fibrosis transmembrane conductance regulator (CFTR).…”

Distribution of PACAP and PAC1 Receptor in the Human Eye

“…As PACAP is a cAMP stimulating peptide, it can be assumed that the neuropeptide plays a role endogenously in the aqueous humor production. Furthermore, PACAP and its receptors have also been shown to act on chloride channels, which are essential in the production of aqueous humor, independently from the cAMP pathway (Alshafie et al 2014 ; Derand et al 2004 ; Leung et al 2001 ; Martinez-Rojas et al 2021 ). The role of PACAP has been implied not only in the production, but also in the absorption of the aqueous humor, as our most recent data have provided evidence that PACAP treatment leads to reduced intraocular pressure in a rat model of glaucoma (Szabo et al 2021 ).…”

Distribution of PACAP and PAC1 Receptor in the Human Eye

“…As PACAP is a cAMP stimulating peptide, it can be assumed that the neuropeptide plays a role endogenously in the aqueous humour production. Furthermore, PACAP and its receptors have also been shown to act on chloride channels, which are essential in the production of aqueous humour, independently from the cAMP pathway (Alsha e et al 2014; Derand et al 2004;Leung et al 2001;Martinez-Rojas et al 2021). The role of PACAP has been implied not only in the production, but also in the absorption of the aqueous humour, as our most recent data have provided evidence that PACAP treatment leads to reduced intraocular pressure in a rat model of glaucoma (Szabo et al 2021).…”