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Antagonism of rat beta -cell voltage-dependent K+ currents by exendin-4 requires dual activation of the cAMP/PKA and PI3 kinase signalling pathways.

MacDonald, Patrick LU ; Wang, Xiaolin; Xia, Fuzhen; El-Kholy, Wasim; Targonsky, Elisha; Tsushima, Robert G. and Wheeler, Michael B. (2003) In Journal of Biological Chemistry 278(52). p.52446-52453
Abstract
Antagonism of voltage-dependent K+ (Kv) currents in pancreatic {beta}-cells may contribute to the ability of glucagon-like peptide-1 (GLP-1) to stimulate insulin secretion. The mechanism and signaling pathway regulating these currents in rat {beta}-cells were investigated using the GLP-1 receptor agonist exendin 4. Inhibition of Kv currents resulted from a 20-mV leftward shift in the voltage dependence of steady-state inactivation. Blocking cAMP or protein kinase A (PKA) signaling (Rp-cAMP and H-89, respectively) prevented the inhibition of currents by exendin 4. However, direct activation of this pathway alone by intracellular dialysis of cAMP or the PKA catalytic subunit (cPKA) could not inhibit currents, implicating a role for... (More)
Antagonism of voltage-dependent K+ (Kv) currents in pancreatic {beta}-cells may contribute to the ability of glucagon-like peptide-1 (GLP-1) to stimulate insulin secretion. The mechanism and signaling pathway regulating these currents in rat {beta}-cells were investigated using the GLP-1 receptor agonist exendin 4. Inhibition of Kv currents resulted from a 20-mV leftward shift in the voltage dependence of steady-state inactivation. Blocking cAMP or protein kinase A (PKA) signaling (Rp-cAMP and H-89, respectively) prevented the inhibition of currents by exendin 4. However, direct activation of this pathway alone by intracellular dialysis of cAMP or the PKA catalytic subunit (cPKA) could not inhibit currents, implicating a role for alternative signaling pathways. A number of phosphorylation sites associated with phosphatidylinositol 3 (PI3)-kinase activation were up-regulated in GLP-1-treated MIN6 insulinoma cells, and the PI3 kinase inhibitor wortmannin could prevent antagonism of {beta}-cell currents by exendin 4. Antagonists of Src family kinases (PP1) and the epidermal growth factor (EGF) receptor (AG1478) also prevented current inhibition by exendin 4, demonstrating a role for Src kinase-mediated trans-activation of the EGF tyrosine kinase receptor. Accordingly, the EGF receptor agonist betacellulin could replicate the effects of exendin 4 in the presence of elevated intracellular cAMP. Downstream, the PKC{zeta} pseudosubstrate inhibitor could prevent current inhibition by exendin 4. Therefore, antagonism of {beta}-cell Kv currents by GLP-1 receptor activation requires both cAMP/PKA and PI3 kinase/PKC{zeta} signaling via trans-activation of the EGF receptor. This represents a novel dual pathway for the control of Kv currents by G protein-coupled receptors. (Less)
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author
publishing date
type
Contribution to journal
publication status
published
subject
in
Journal of Biological Chemistry
volume
278
issue
52
pages
52446 - 52453
publisher
ASBMB
external identifiers
  • scopus:0346732301
ISSN
1083-351X
DOI
10.1074/jbc.M307612200
language
English
LU publication?
no
id
07c94af4-b5ca-4a41-a7e9-f3be75edb37e (old id 118237)
date added to LUP
2007-07-17 11:39:03
date last changed
2018-01-07 05:59:06
@article{07c94af4-b5ca-4a41-a7e9-f3be75edb37e,
  abstract     = {Antagonism of voltage-dependent K+ (Kv) currents in pancreatic {beta}-cells may contribute to the ability of glucagon-like peptide-1 (GLP-1) to stimulate insulin secretion. The mechanism and signaling pathway regulating these currents in rat {beta}-cells were investigated using the GLP-1 receptor agonist exendin 4. Inhibition of Kv currents resulted from a 20-mV leftward shift in the voltage dependence of steady-state inactivation. Blocking cAMP or protein kinase A (PKA) signaling (Rp-cAMP and H-89, respectively) prevented the inhibition of currents by exendin 4. However, direct activation of this pathway alone by intracellular dialysis of cAMP or the PKA catalytic subunit (cPKA) could not inhibit currents, implicating a role for alternative signaling pathways. A number of phosphorylation sites associated with phosphatidylinositol 3 (PI3)-kinase activation were up-regulated in GLP-1-treated MIN6 insulinoma cells, and the PI3 kinase inhibitor wortmannin could prevent antagonism of {beta}-cell currents by exendin 4. Antagonists of Src family kinases (PP1) and the epidermal growth factor (EGF) receptor (AG1478) also prevented current inhibition by exendin 4, demonstrating a role for Src kinase-mediated trans-activation of the EGF tyrosine kinase receptor. Accordingly, the EGF receptor agonist betacellulin could replicate the effects of exendin 4 in the presence of elevated intracellular cAMP. Downstream, the PKC{zeta} pseudosubstrate inhibitor could prevent current inhibition by exendin 4. Therefore, antagonism of {beta}-cell Kv currents by GLP-1 receptor activation requires both cAMP/PKA and PI3 kinase/PKC{zeta} signaling via trans-activation of the EGF receptor. This represents a novel dual pathway for the control of Kv currents by G protein-coupled receptors.},
  author       = {MacDonald, Patrick and Wang, Xiaolin and Xia, Fuzhen and El-Kholy, Wasim and Targonsky, Elisha and Tsushima, Robert G. and Wheeler, Michael B.},
  issn         = {1083-351X},
  language     = {eng},
  number       = {52},
  pages        = {52446--52453},
  publisher    = {ASBMB},
  series       = {Journal of Biological Chemistry},
  title        = {Antagonism of rat beta -cell voltage-dependent K+ currents by exendin-4 requires dual activation of the cAMP/PKA and PI3 kinase signalling pathways.},
  url          = {http://dx.doi.org/10.1074/jbc.M307612200},
  volume       = {278},
  year         = {2003},
}