β-Adrenergic Activation of Electrogenic K+ and Cl- Secretion in Guinea Pig Distal Colonic Epithelium Proceeds via Separate cAMP Signaling Pathways

Authors

Susan T. Halm, Wright State University - Main CampusFollow
Jin Zhang, Wright State University - Main CampusFollow
Dan R. Halm, Wright State University - Main CampusFollow

Document Type

Article

Publication Date

7-2010

Abstract

Adrenergic stimulation of isolated guinea pig distal colonic mucosa produced transient Cl^- and sustained K⁺ secretion. Transient short-circuit current (I_sc) depended on β₂-adrenergic receptors (β₂-AdrR), and sustained I_sc relies on a β₁-AdrR/β₂-AdrR complex. Epinephrine (epi) increased cAMP content with a biphasic time course similar to changes in epi-activated I_sc (^epiI_sc). Inhibition of transmembrane adenylyl cyclases (tmACs) reduced peak ^epiI_sc and cAMP to near zero without decreasing sustained ^epiI_sc, consistent with cAMP from tmAC signaling for only Cl^- secretion. Inhibition of soluble adenylyl cyclase (sAC) reduced sustained ^epiI_sc and cAMP to near zero without decreasing peak ^epiI_sc or cAMP, consistent with cAMP from sAC signaling for K⁺ secretion. Sensitivity to phosphodiesterase (PDE) inhibitors and peptide YY (PYY) stimulation further supported separate signaling for the two components. PDE3 or PDE4 inhibitors enhanced peak ^epiI_sc but not sustained ^epiI_sc, consistent with these PDEs as part of the β₂-AdrR signaling domain. PYY suppressed peak ^epiI_sc in a pertussis toxin (PTx)-sensitive manner, supporting Gα_i-dependent inhibition of tmACs producing cAMP for Cl^- secretion. Since PYY or PTx did not alter sustained ^epiI_sc, signaling for K⁺ secretion occurred via a Gα_i-independent mechanism. Presence of multiple sAC variants in colonic epithelial cells was supported by domain-specific antibodies. Responses to specific activators and inhibitors suggested that protein kinase A was not involved in activating peak or sustained components of ^epiI_sc, but the cAMP-dependent guanine nucleotide exchange factor, Epac, may contribute. Thus β-adrenergic activation of electrogenic Cl^- and K⁺ secretion, respectively, required tmAC- and sAC-dependent signaling pathways.

Repository Citation

Halm, S. T., Zhang, J., & Halm, D. R. (2010). β-Adrenergic Activation of Electrogenic K+ and Cl- Secretion in Guinea Pig Distal Colonic Epithelium Proceeds via Separate cAMP Signaling Pathways. American Journal of Physiology - Gastrointestinal and Liver Physiology, 299 (1), G81-G95.
https://corescholar.libraries.wright.edu/ncbp/991

DOI

10.1152/ajpgi.00035.2010