Protein kinases talk to lipid phosphatases at the synapse.

Abstract

The ability to police membrane traffic in space and time reaches an especially high level of sophistication at presynaptic nerve terminals, where synaptic vesicles (SVs) containing nonpeptide neurotransmitters are found in a state of flux between the presynaptic plasma membrane and various internal pools. Commonly termed the SV cycle, this movement of SV contents and membrane components at axon terminals comprises three stages, namely exocytosis, endocytosis, and vesicle recycling. At the center of this dynamic picture is the lipid–protein interface, where physical and biochemical interactions between lipids and proteins determine the course of membrane traffic (1). These interactions are, in turn, regulated by a cycle of lipid and protein phosphorylation/dephosphorylation in response to appropriate cues (2). In a recent issue of PNAS, Lee et al. (3) reported findings that shed light on a key aspect of synaptic membrane traffic. By using purified synaptojanin 1, they demonstrated that this lipid phosphatase, implicated in the uncoating of retrieved SVs during clathrin-mediated endocytosis, is subject to regulation by phosphorylation/dephosphorylation like other proteins of the endocytic machinery (4). Protein phosphorylation plays a central role in the control of the SV cycle. Synapsin, whose phosphorylation promotes the release SVs from the reserve pool in stimulated nerve terminals, is arguably the best-characterized phosphoprotein in this regard (5). Evidence continues to accumulate for the phosphorylation-dependent regulation of endocytic machinery components as well. Here protein kinases appear to function primarily as negative modulators, providing tonic inhibition of SV endocytosis in resting neurons. This inhibition is reversed by nerve terminal stimulation, which triggers endocytosis through the coordinate Ca2+-dependent dephosphorylation of a heterogeneous group of phosphoproteins known as dephosphins (4). Synaptojanin 1, a polyphosphoinositide phosphatase, belongs to this group. While phosphoproteins have understandably garnered …