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

Abstract

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-b, 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 actincontaining 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.

Involvement of Protein Kinase C-ε in Activity-Dependent Potentiation of Large Dense-Core Vesicle Exocytosis in Chromaffin Cells

“…MARCKS, which is known to regulate F-actin dynamics, has been reported to be phosphorylated by many kinases, such as mitogen-activated protein kinases, cyclin-dependent kinases, PKA, Rho kinase, as well as PKC (Arbuzova et al, 2002;Sasaki, 2003). Phospho-MARCKS antibody that we used in the present study recognizes residues phosphorylated by PKC (Heemskerk et al, 1993).…”

MARCKS in Advanced Stages of Neural Retina Histogenesis

“…The high MARCKS concentration existing in the IPL could be related with the traffi c and release of neurotransmitters, a process involving actin fi lament reorganization that facilitates synaptic vesicle fusion with the membrane [Aderem, 1995]. Besides the classical phosphorylations achieved by PKC in neuron terminals [Vaughan et al, 1998], rho-kinase can phosphorylate other serines located at MARCKS effector domain and promote the release of some neurotransmitters [Sasaki, 2003]. It is interesting to keep in mind the asso-ciation of PKC with developing and mature plexiform layers in chickens [Caminos et al, 1999].…”

CFTR, Mucins, and Mucus Obstruction in Cystic Fibrosis

“…The main downstream effector of ROCK in airway goblet cells appears to be myosin light chain kinase (MLCK) (Seminario-Vidal et al 2009;Kreda et al 2010), which is essential in actomyosin cytoskeleton remodeling during mucin granule exocytosis Kreda et al 2010). However, other ROCK targets involved in agonist-stimulated granule secretion have been described; for example, ROCK has been described to regulate MARCKS by phosphorylation (Sasaki 2003). MARCKS is also activated downstream from PKC and has been reported to regulate mucin granule exocytosis (Li et al 2001;Singer et al 2004).…”