A novel lipid-anchored A-kinase Anchoring Protein facilitates cAMP-responsive membrane events

EMBO J. 1998 Apr 15;17(8):2261-72. doi: 10.1093/emboj/17.8.2261.

Abstract

Compartmentalization of protein kinases with substrates is a mechanism that may promote specificity of intracellular phosphorylation events. We have cloned a low-molecular weight A-kinase Anchoring Protein, called AKAP18, which targets the cAMP-dependent protein kinase (PKA) to the plasma membrane, and permits functional coupling to the L-type calcium channel. Membrane anchoring is mediated by the first 10 amino acids of AKAP18, and involves residues Gly1, Cys4 and Cys5 which are lipid-modified through myristoylation and dual palmitoylation, respectively. Transient transfection of AKAP18 into HEK-293 cells expressing the cardiac L-type Ca2+ channel promoted a 34 9% increase in cAMP-responsive Ca2+ currents. In contrast, a targeting-deficient mutant of AKAP18 had no effect on Ca2+ currents in response to the application of a cAMP analog. Further studies demonstrate that AKAP18 facilitates GLP-1-mediated insulin secretion in a pancreatic beta cell line (RINm5F), suggesting that membrane anchoring of the kinase participates in physiologically relevant cAMP-responsive events that may involve ion channel activation.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • A Kinase Anchor Proteins
  • Adaptor Proteins, Signal Transducing*
  • Amino Acid Sequence
  • Animals
  • Base Sequence
  • Binding Sites
  • Calcium Channels / physiology
  • Carrier Proteins*
  • Cell Line
  • Cell Membrane / metabolism
  • Cloning, Molecular
  • Cyclic AMP / metabolism*
  • Cyclic AMP-Dependent Protein Kinases / metabolism*
  • DNA, Complementary
  • Electric Conductivity
  • Glucagon / metabolism
  • Glucagon-Like Peptide 1
  • Humans
  • Insulin / metabolism
  • Insulin Secretion
  • Membrane Proteins*
  • Mice
  • Molecular Sequence Data
  • Peptide Fragments / metabolism
  • Peptide Mapping
  • Protein Kinases / genetics
  • Protein Kinases / metabolism*
  • Protein Precursors / metabolism
  • Sequence Homology, Amino Acid

Substances

  • A Kinase Anchor Proteins
  • AKAP7 protein, human
  • Adaptor Proteins, Signal Transducing
  • Akap7 protein, mouse
  • Calcium Channels
  • Carrier Proteins
  • DNA, Complementary
  • Insulin
  • Membrane Proteins
  • Peptide Fragments
  • Protein Precursors
  • Glucagon-Like Peptide 1
  • Glucagon
  • Cyclic AMP
  • Protein Kinases
  • Cyclic AMP-Dependent Protein Kinases

Associated data

  • GENBANK/AF047715
  • GENBANK/AF047716