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.
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.
D000818:Animals; D005089:Exocytosis / Q000502:physiology*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D019814:Myristic Acid / Q000378:metabolism; D000076250:Myristoylated Alanine-Rich C Kinase Substrate; D016900:Neurofilament Proteins / Q000737:chemistry / Q000378:metabolism*; D009474:Neurons / Q000201:enzymology* / Q000378:metabolism; D018377:Neurotransmitter Agents / Q000378:metabolism*; D010766:Phosphorylation; D011493:Protein Kinase C / Q000378:metabolism* / Q000502:physiology; D017346:Protein Serine-Threonine Kinases / Q000502:physiology*; D011506:Proteins / Q000378:metabolism* / Q000502:physiology; D013379:Substrate Specificity / Q000502:physiology; D054460:rho-Associated Kinases
D047908:Intracellular Signaling Peptides and Proteins; C000619710:MARCKS protein, human; D008565:Membrane Proteins; D016900:Neurofilament Proteins; D018377:Neurotransmitter Agents; D011506:Proteins; D019814:Myristic Acid; D000076250:Myristoylated Alanine-Rich C Kinase Substrate; D017346:Protein Serine-Threonine Kinases; D054460:rho-Associated Kinases; D011493:Protein Kinase C