Nesprin-1alpha contributes to the targeting of mAKAP to the cardiac myocyte nuclear envelope

Exp Cell Res. 2005 Feb 15;303(2):388-99. doi: 10.1016/j.yexcr.2004.10.009.


Muscle A-kinase anchoring protein (mAKAP) is a scaffold protein found principally at the nuclear envelope of striated myocytes. mAKAP maintains a complex consisting of multiple signal transduction molecules including the cAMP-dependent protein kinase A, the ryanodine receptor calcium release channel, phosphodiesterase type 4D3, and protein phosphatase 2A. By an unknown mechanism, a domain containing spectrin repeats is responsible for targeting mAKAP to the nuclear envelope. We now demonstrate that the integral membrane protein nesprin-1alpha serves as a receptor for mAKAP on the nuclear envelope in cardiac myocytes. Nesprin-1alpha is inserted into the nuclear envelope by a conserved, C-terminal, klarsicht-related transmembrane domain and forms homodimers by the binding of an amino-terminal spectrin repeat domain. Through the direct binding of the nesprin-1alpha amino-terminal dimerization domain to the third mAKAP spectrin repeat, nesprin-1alpha targets mAKAP to the nuclear envelope. In turn, overexpression of these spectrin repeat domains in myocytes can displace mAKAP from nesprin-1alpha.

Publication types

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

MeSH terms

  • 3',5'-Cyclic-AMP Phosphodiesterases / metabolism
  • A Kinase Anchor Proteins
  • Adaptor Proteins, Signal Transducing / chemistry
  • Adaptor Proteins, Signal Transducing / genetics
  • Adaptor Proteins, Signal Transducing / metabolism*
  • Amino Acid Substitution
  • Animals
  • Base Sequence
  • Binding, Competitive
  • COS Cells
  • Cyclic Nucleotide Phosphodiesterases, Type 4
  • DNA, Complementary / genetics
  • Dimerization
  • Multiprotein Complexes
  • Mutagenesis, Site-Directed
  • Myocytes, Cardiac / metabolism*
  • Nerve Tissue Proteins / chemistry
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism*
  • Nuclear Envelope / metabolism*
  • Nuclear Proteins / chemistry
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism*
  • Point Mutation
  • Protein Structure, Quaternary
  • Rats
  • Recombinant Proteins / chemistry
  • Recombinant Proteins / genetics
  • Recombinant Proteins / metabolism
  • Signal Transduction
  • Transfection


  • A Kinase Anchor Proteins
  • Adaptor Proteins, Signal Transducing
  • Akap6 protein, rat
  • DNA, Complementary
  • Multiprotein Complexes
  • Nerve Tissue Proteins
  • Nuclear Proteins
  • Recombinant Proteins
  • Syne1 protein, rat
  • 3',5'-Cyclic-AMP Phosphodiesterases
  • Cyclic Nucleotide Phosphodiesterases, Type 4