Antagonism of rat beta -cell voltage-dependent K+ currents by exendin-4 requires dual activation of the cAMP/PKA and PI3 kinase signalling pathways.
(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)
Please use this url to cite or link to this publication:
https://lup.lub.lu.se/record/118237
- author
- MacDonald, Patrick LU ; Wang, Xiaolin ; Xia, Fuzhen ; El-Kholy, Wasim ; Targonsky, Elisha ; Tsushima, Robert G. and Wheeler, Michael B.
- publishing date
- 2003
- type
- Contribution to journal
- publication status
- published
- subject
- in
- Journal of Biological Chemistry
- volume
- 278
- issue
- 52
- pages
- 52446 - 52453
- publisher
- American Society for Biochemistry and Molecular Biology
- 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
- 2016-04-01 12:15:29
- date last changed
- 2022-04-21 04:53:19
@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 = {{American Society for Biochemistry and Molecular Biology}},
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}},
doi = {{10.1074/jbc.M307612200}},
volume = {{278}},
year = {{2003}},
}