A presynaptic role for the ADP ribosylation factor (ARF)-specific GDP/GTP exchange factor msec7-1

Abstract

ADP ribosylation factors (ARFs) represent a family of small monomeric G proteins that switch from an inactive, GDP-bound state to an active, GTP-bound state. One member of this family, ARF6, translocates on activation from intracellular compartments to the plasma membrane and has been implicated in regulated exocytosis in neuroendocrine cells. Because GDP release in vivo is rather slow, ARF activation is facilitated by specific guanine nucleotide exchange factors like cytohesin-1 or ARNO. Here we show that msec7-1, a rat homologue of cytohesin-1, translocates ARF6 to the plasma membrane in living cells. Overexpression of msec7-1 leads to an increase in basal synaptic transmission at the Xenopus neuromuscular junction. msec7-1-containing synapses have a 5-fold higher frequency of spontaneous synaptic currents than control synapses. On stimulation, the amplitudes of the resulting evoked postsynaptic currents of msec7-1-overexpressing neurons are increased as well. However, further stimulation leads to a decline in amplitudes approaching the values of control synapses. This transient effect on amplitude is strongly reduced on overexpression of msec7-1E157K, a mutant incapable of translocating ARFs. Our results provide evidence that small G proteins of the ARF family and activating factors like msec7-1 play an important role in synaptic transmission, most likely by making more vesicles available for fusion at the plasma membrane.

FRMD4A–cytohesin signaling modulates the cellular release of tau

“…FRMD4A-cytohesin signaling enhances translocation of active Arf6 to the plasma membrane (Ashery et al, 1999;Hafner et al, 2006;Ikenouchi and Umeda, 2010). Similar to overexpression of FRMD4A, overexpression of wild-type Arf6 in HEK293T cells expressing tauGLuc1/2 cells strongly enhanced both intracellular tau dimerization and tau secretion.…”

“…Whereas cytohesins (also known as mSec7 proteins) have a role in vesicle transport at the presynaptic terminal (Ashery et al, 1999;Neeb et al, 1999), the role of FRMD4A in neurons remains poorly understood. We transduced cultures of mouse cortical neurons with lentivirus expressing FRMD4A short hairpin RNA (shRNA), resulting in 99% reduction of endogenous FRMD4A mRNA levels (Fig.…”

ARF6 and EFA6A Regulate the Development and Maintenance of Dendritic Spines

“…In the nervous system, ARF6 has been shown to suppress the branching of dendrites and axons in hippocampal neurons (Hernandez-Deviez et al, 2002;Hernandez-Deviez et al, 2004), promote neurotransmitter release at the Xenopus neuromuscular junction (Ashery et al, 1999), and stimulate clathrin/AP-2 recruitment to synaptic membranes by activating phosphatidylinositol 4-phosphate 5-kinase (PIP5-kinase) type I␥ (Krauss et al, 2003). ARF6-dependent regulation of neurite branching suggests involvement in early neuronal morphogenesis.…”

Genetic risk factors of Alzheimer's disease and cell-to-cell transmission of Tau

“…Cytohesins function in various cellular processes including insulin receptor signaling 48 , integrin trafficking and cell migration 46 . Importantly, they also regulate neurotransmission 47 and membrane trafficking 49 at the presynaptic terminal, probably via their interaction with Munc13s 50 , that are proteins essential for synaptic vesicle priming 51 . As Tau secretion is related to neurotransmitter release 2,52 , it seems plausible that the changes we see in Tau secretion with modulation of FRMD4A-cytohesin pathway are connected to synaptic vesicle release.…”

“…Cytohesins bind FRMD4A 44 and activate the small GTPase Arf6 46 promoting its translocation to the plasma membrane 47 . Cytohesins function in various cellular processes including insulin receptor signaling 48 , integrin trafficking and cell migration 46 .…”