HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: 586/5/1307    most recent jphysiol.2007.143818v1 Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Kang, G. Articles by Holz, G. G. Search for Related Content PubMed PubMed Citation Articles by Kang, G. Articles by Holz, G. G. Related Collections Cellular

¹ Departments of Physiology and Neuroscience
² Pediatrics
³ Pharmacology, New York University School of Medicine, New York, NY, USA

Protein kinase A (PKA)-independent actions of adenosine 3',5'-cyclic monophosphate (cAMP) are mediated by Epac, a cAMP sensor expressed in pancreatic β-cells. Evidence that Epac might mediate the cAMP-dependent inhibition of β-cell ATP-sensitive K⁺ channels (K_ATP) was provided by one prior study of human β-cells and a rat insulin-secreting cell line (INS-1 cells) in which it was demonstrated that an Epac-selective cAMP analogue (ESCA) inhibited a sulphonylurea-sensitive K⁺ current measured under conditions of whole-cell recording. Using excised patches of plasma membrane derived from human β-cells and rat INS-1 cells, we now report that 2'-O-Me-cAMP, an ESCA that activates Epac but not PKA, sensitizes single K_ATP channels to the inhibitory effect of ATP, thereby reducing channel activity. In the presence of 2'-O-Me-cAMP (50 µM), the dose–response relationship describing ATP-dependent inhibition of K_ATP channel activity (NP_o) is left-shifted such that the concentration of ATP producing 50% inhibition (IC₅₀) is reduced from 22 µM to 1 µM for human β-cells, and from 14 µM to 4 µM for rat INS-1 cells. Conversely, when patches are exposed to a fixed concentration of ATP (10 µM), the administration of 2'-O-Me-cAMP inhibits channel activity in a dose-dependent and reversible manner (IC₅₀ 12 µM for both cell types). A cyclic nucleotide phosphodiesterase-resistant ESCA (Sp-8-pCPT-2'-O-Me-cAMPS) also inhibits K_ATP channel activity, thereby demonstrating that the inhibitory actions of ESCAs reported here are unlikely to arise as a consequence of their hydrolysis to bioactive derivatives of adenosine. On the basis of such findings it is concluded that there exists in human β-cells and rat INS-1 cells a novel form of ion channel modulation in which the ATP sensitivity of K_ATP channels is regulated by Epac.

(Received 24 August 2007; accepted after revision 10 January 2008; first published online 17 January 2008)
Corresponding author G. G. Holz: Medical Sciences Building Room 442, 550 First Avenue, New York, NY 10016, USA. Email: holzg01{at}popmail.med.nyu.edu

This article has been cited by other articles:

				H. Liu, J. A. Enyeart, and J. J. Enyeart ACTH Inhibits bTREK-1 K+ Channels through Multiple cAMP-dependent Signaling Pathways J. Gen. Physiol., August 1, 2008; 132(2): 279 - 294. [Abstract] [Full Text] [PDF]