New aspects of neurotransmitter release and exocytosis: Rho-kinase-dependent myristoylated alanine-rich C-kinase substrate phosphorylation and regulation of neurofilament structure in neuronal cells

J Pharmacol Sci. 2003 Sep;93(1):35-40. doi: 10.1254/jphs.93.35.

Abstract

Myristoylated alanine-rich C-kinase substrate (MARCKS) is an actin-binding protein whose function may be regulated by the phosphorylation of multiple sites, in which the phosphorylation site domain (PSD) is recognized to have three or four PKC-dependent sites. Recently, it is considered that MARCKS is implicated in some neuronal functions, such as synaptic vesicle trafficking and neurotransmitter release, through regulation of the actin-containing cytoskeletal structure; this is based on the experimental results with short-term or prolonged pretreatment with phorbol esters and treatment by protein kinase C (PKC) inhibitor. However, the precise molecular mechanism is yet obscure. Recently, we have demonstrated that MARCKS is phosphorylated at Ser159 in PSD by Rho-kinase in vitro and that the phosphorylation occurred in neuronal cells upon stimulation with lysophosphatidic acid (LPA), and its phosphorylation was inhibited by a novel and specific Rho-kinase inhibitor, H-1152. Our results allow us to speculate that a preinflammatory substance, such as LPA, interleukin 1-beta, and bradykinin, augments MARCKS phosphorylation in a novel signal transduction pathway besides the PKC-involved one, and thereby induces the release of a neurotransmitter through a reorganization of actin-containing microfilaments at the cell periphery, the so-called "active zone". In this section, I address a novel mechanism for MARCKS phosphorylation and its related cellular function.

Publication types

  • Review

MeSH terms

  • Animals
  • Exocytosis / physiology*
  • Humans
  • Intracellular Signaling Peptides and Proteins*
  • Membrane Proteins*
  • Myristic Acid / metabolism
  • Myristoylated Alanine-Rich C Kinase Substrate
  • Neurofilament Proteins / chemistry
  • Neurofilament Proteins / metabolism*
  • Neurons / enzymology*
  • Neurons / metabolism
  • Neurotransmitter Agents / metabolism*
  • Phosphorylation
  • Protein Kinase C / metabolism*
  • Protein Kinase C / physiology
  • Protein Serine-Threonine Kinases / physiology*
  • Proteins / metabolism*
  • Proteins / physiology
  • Substrate Specificity / physiology
  • rho-Associated Kinases

Substances

  • Intracellular Signaling Peptides and Proteins
  • MARCKS protein, human
  • Membrane Proteins
  • Neurofilament Proteins
  • Neurotransmitter Agents
  • Proteins
  • Myristic Acid
  • Myristoylated Alanine-Rich C Kinase Substrate
  • Protein Serine-Threonine Kinases
  • rho-Associated Kinases
  • Protein Kinase C