β-Adrenergic Activation of Electrogenic K+ and Cl- Secretion in Guinea Pig Distal Colonic Epithelium Proceeds via Separate cAMP Signaling Pathways
Adrenergic stimulation of isolated guinea pig distal colonic mucosa produced transient Cl- and sustained K+ secretion. Transient short-circuit current (Isc) depended on β2-adrenergic receptors (β2-AdrR), and sustained Isc relies on a β1-AdrR/β2-AdrR complex. Epinephrine (epi) increased cAMP content with a biphasic time course similar to changes in epi-activated Isc (epiIsc). Inhibition of transmembrane adenylyl cyclases (tmACs) reduced peak epiIsc and cAMP to near zero without decreasing sustained epiIsc, consistent with cAMP from tmAC signaling for only Cl- secretion. Inhibition of soluble adenylyl cyclase (sAC) reduced sustained epiIsc and cAMP to near zero without decreasing peak epiIsc 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 epiIsc but not sustained epiIsc, consistent with these PDEs as part of the β2-AdrR signaling domain. PYY suppressed peak epiIsc in a pertussis toxin (PTx)-sensitive manner, supporting Gαi-dependent inhibition of tmACs producing cAMP for Cl- secretion. Since PYY or PTx did not alter sustained epiIsc, signaling for K+ secretion occurred via a Gαi-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 epiIsc, 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.
Halm, S. T.,
& 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.