Myosin Va cooperates with PKA RIalpha to mediate maintenance of the endplate in vivo

Proc Natl Acad Sci U S A. 2010 Feb 2;107(5):2031-6. doi: 10.1073/pnas.0914087107. Epub 2010 Jan 19.

Abstract

Myosin V motor proteins facilitate recycling of synaptic receptors, including AMPA and acetylcholine receptors, in central and peripheral synapses, respectively. To shed light on the regulation of receptor recycling, we employed in vivo imaging of mouse neuromuscular synapses. We found that myosin Va cooperates with PKA on the postsynapse to maintain size and integrity of the synapse; this cooperation also regulated the lifetime of acetylcholine receptors. Myosin Va and PKA colocalized in subsynaptic enrichments. These accumulations were crucial for synaptic integrity and proper cAMP signaling, and were dependent on AKAP function, myosin Va, and an intact actin cytoskeleton. The neuropeptide and cAMP agonist, calcitonin-gene related peptide, rescued fragmentation of synapses upon denervation. We hypothesize that neuronal ligands trigger local activation of PKA, which in turn controls synaptic integrity and turnover of receptors. To this end, myosin Va mediates correct positioning of PKA in a postsynaptic microdomain, presumably by tethering PKA to the actin cytoskeleton.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • A Kinase Anchor Proteins / antagonists & inhibitors
  • A Kinase Anchor Proteins / metabolism
  • Actins / metabolism
  • Animals
  • Calcitonin Gene-Related Peptide / pharmacology
  • Cyclic AMP / metabolism
  • Cyclic AMP-Dependent Protein Kinase RIalpha Subunit / genetics
  • Cyclic AMP-Dependent Protein Kinase RIalpha Subunit / metabolism*
  • Denervation
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Microscopy, Confocal
  • Molecular Motor Proteins / metabolism
  • Motor Endplate / drug effects
  • Motor Endplate / metabolism*
  • Myosin Heavy Chains / antagonists & inhibitors
  • Myosin Heavy Chains / metabolism*
  • Myosin Type V / antagonists & inhibitors
  • Myosin Type V / metabolism*
  • Neuronal Plasticity
  • Receptors, Cholinergic / metabolism
  • Signal Transduction

Substances

  • A Kinase Anchor Proteins
  • Actins
  • Cyclic AMP-Dependent Protein Kinase RIalpha Subunit
  • Molecular Motor Proteins
  • Myo5a protein, mouse
  • Receptors, Cholinergic
  • Cyclic AMP
  • Myosin Type V
  • Myosin Heavy Chains
  • Calcitonin Gene-Related Peptide