Ca2+ -myristoyl switch in neuronal calcium sensor-1: a role of C-terminal segment

CNS Neurol Disord Drug Targets. 2015;14(4):437-51. doi: 10.2174/1871527314666150225143403.

Abstract

NCS1 (neuronal calcium sensor-1) is a Ca(2+)-myristoyl switch protein of the NCS protein family involved in synaptic plasticity and neurotransmission via Ca(2+)-dependent regulation of dopamine D2 receptor and associated Gprotein coupled receptor kinase (GRK)-2. Overexpression of NCS1 in synaptic terminals results in accumulation of membrane-bound protein and its redundant regulatory activity associated with neurological disorders. Here, we have demonstrated that bovine photoreceptors contain NCS1 that is capable of a partially irreversible interaction with isolated photoreceptor membranes and implicated in Ca(2+)-dependent binding and regulation of GRK1 in vitro. Using NCS1- recoverin C-terminal chimeric construct (NR), it was found that the Ca(2+)-myristoyl switch of NCS1 is affected by its C-terminal segment downstream the fourth EF-loop of the protein, which is variable within the NCS family. NR retains structural stability and sensitivity to Ca(2+), but interacts with photoreceptor membranes with lower affinity in a Ca(2+)- dependent fully reversible manner and displays altered GRK1 modulation. These data combined with fluorescent probing of surface hydrophobicity of NCS1, NR and recoverin suggest that the C-terminal segment of NCS1 regulates reuptake of myristoyl group under Ca(2+)-free conditions and participates in organization of the target-binding pocket of the protein. We point out a putative role of NCS1 in photoreceptors as a modulator of GRK activity and propose targeting of the C-terminal segment of NCS1 as an appropriate way for selective suppression of excessive membrane accumulation and aberrant activity of the protein in neurons associated with central nervous system dysfunctions.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Brain / metabolism*
  • Calcium / metabolism*
  • Calcium Signaling / physiology*
  • Cattle
  • Cell Membrane / metabolism
  • G-Protein-Coupled Receptor Kinase 1 / metabolism
  • Neuronal Calcium-Sensor Proteins / metabolism*
  • Neurons / metabolism*
  • Photoreceptor Cells / metabolism
  • Reactive Oxygen Species / metabolism

Substances

  • Neuronal Calcium-Sensor Proteins
  • Reactive Oxygen Species
  • G-Protein-Coupled Receptor Kinase 1
  • Calcium