The EFA6 Family: Guanine Nucleotide Exchange Factors for ADP Ribosylation Factor 6 at Neuronal Synapses

Abstract

ADP ribosylation factor 6 (ARF6) is a member of the ARF family of small GTPases, which mediates a variety of neuronal functions accompanying the structural changes of developing and mature neurons through its regulation of actin cytoskeleton reorganization and membrane traffi c. The activation of ARF6 is strictly regulated by guanine nucleotide exchange factors (GEFs). The EFA6 family is the fi rst member that was identifi ed to be a specifi c GEF for ARF6 and comprises four structurally related polypeptides (EFA6A, EFA6B, EFA6C and EFA6D). Since the cellular and subcelllular localization of GEFs is a critical determinant for the spatiotemporal activation of ARF6 in neurons, I have focused on the EFA6 family from the anatomical point of view to understand the neuronal functions of ARF6. Three members of the EFA6 family (EFA6A, EFA6C and EFA6D) are abundantly expressed in the mouse brain with distinct spatiotemporal patterns. Interestingly, they are enriched particularly in the postsynaptic density fraction, shedding light on the importance of the EFA-ARF6 pathway in neuronal synapses. Here, I will review the recent advances in the expression and functions of the EFA6 family in the nervous system. small GTPase; ADP ribosylation factor; dendrite; postsynaptic density.Tohoku

ADP Ribosylation Factor 6 (ARF6) Promotes Acrosomal Exocytosis by Modulating Lipid Turnover and Rab3A Activation

“…All ARF6 GEFs possess a pleckstrin homology domain that serves as a binding site for specific phosphoinositides and/or partner proteins. They are recruited to the membranes through an interaction with PIP 2 or PIP 3 , depending on the different affinities of pleckstrin homology domains for these phospholipids (83,84). The synthesis of PIP 2 and/or PIP 3 may be one of the major mechanisms through which ARF6 is activated at the membrane in response to agonist stimulation of cells (85).…”

ADP-ribosylation Factor 6 (ARF6) Bidirectionally Regulates Dendritic Spine Formation Depending on Neuronal Maturation and Activity

“…Growing evidence suggests that ARF6 activation is precisely regulated by ARF6 GEFs in a spatiotemporal manner, leading to neuronal development and synapse formation (7,50). Cytohesin1 and -2, EFA6A-D, and brefeldin A-resistant ARF-GEF1-3 are well known positive regulators for ARF6 activation (51).…”

ARF6 Directs Axon Transport and Traffic of Integrins and Regulates Axon Growth in Adult DRG Neurons

“…This suggests that ACAP1 promotes integrin-dependent outgrowth, functioning through its ARF6 GAP activity and not by its function as a coat protein. We next investigated the effects of activating ARF6 using two ARF6 GEFs that are expressed in neurons, EFA6 (Sakagami, 2008) and ARNO (Hernández-Deviez et al, 2002Hernández-Deviez and Wilson, 2005). EFA6 has ARF6-specific GEF activity (Franco et al, 1999;Macia et al, 2001), while ARNO is reported to have some ARF1 GEF activity in vitro, but is considered to be principally an ARF6 GEF (Frank et al, 1998;Venkateswarlu and Cullen, 2000;Macia et al, 2001;Gillingham and Munro, 2007;Hofmann et al, 2007).…”