Drosophila Hsc70-4 Is Critical for Neurotransmitter Exocytosis In Vivo

Abstract

Previous in vitro studies of cysteine-string protein (CSP) imply a potential role for the clathrin-uncoating ATPase Hsc70 in exocytosis. We show that hypomorphic mutations in Drosophila Hsc70-4 (Hsc4) impair nerve-evoked neurotransmitter release, but not synaptic vesicle recycling in vivo. The loss of release can be restored by increasing external or internal Ca(2+) and is caused by a reduced Ca(2+) sensitivity of exocytosis downstream of Ca(2+) entry. Hsc4 and CSP are likely to act in common pathways, as indicated by their in vitro protein interaction, the similar loss of evoked release in individual and double mutants, and genetic interactions causing a loss of release in trans-heterozygous hsc4-csp double mutants. We suggest that Hsc4 and CSP cooperatively augment the probability of release by increasing the Ca(2+) sensitivity of vesicle fusion.

Loss of Hsp70 in Drosophila Is Pleiotropic, With Effects on Thermotolerance, Recovery From Heat Shock and Neurodegeneration

“…In the absence of Hsp70, this association does not occur and a change in the conformation of the temperature-sensitive shi 1 protein may be irreversible. In support of the idea that Hsp70 may substitute for Hsc70-4, Hsp70 is abnormally induced in Hsc70-4 mutant flies when it would otherwise be silent (Elefant and Palter 1999;Bronk et al, 2001). However, if this hypothesis were true it seems that Hsp70-null flies should exhibit paralysis under the same conditions that inactivate shi 1 , and they do not.…”

“…The Hsp70 cognate, Hsc70-4, binds to clathrin and dynamin and participates in the assembly and disassembly of clathrin cages, with mutants showing defects in endocytosis and exocytosis (Schlossman et al 1984;Bronk et al 2001;Newmyer and Schmid 2001;Chang et al 2002;Newmyer et al 2003). In Hsp70 1 flies, perhaps Hsp70 takes the part of Hsc70-4 and associates with clathrin and/or dynamin at high temperature.…”

Cysteine String Protein Monitors Late Steps in Cystic Fibrosis Transmembrane Conductance Regulator Biogenesis

“…These actions of Csp in protein biogenesis represent novel functions for this J-domain containing protein, which was identified initially as an essential factor in calcium-triggered neurotransmitter exocytosis at nerve terminals (19,42). Csp is anchored on the cytoplasmic surface of synaptic vesicle membranes by multiple palmitoylation within its cysteine-rich region, and although the mechanism is not entirely clear, Csp is thought to cooperate with Hsp70 at this site to chaperone the protein interactions necessary for synaptic vesicle fusion (43,44). Indeed, Csp is now recognized to facilitate a variety of regulated exocytic events (for review see Ref.…”

The Upregulation of Cognate and Inducible Heat Shock Proteins in the Anoxic Turtle Brain

“…In the rat brain, Hsc70 (Hsc73) is important in the maintenance of normal synaptic structure (Bronk et al, 2001), in synaptic plasticity, and in GABA neurotransmission (Jin et al, 2003).…”