SNAP-25

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Molecular machinery driving exocytosis in neuromediator release. The core SNARE complex is formed by four α-helices contributed by synaptobrevin, syntaxin and SNAP-25, synaptotagmin serves as a Ca²⁺ sensor and regulates intimately the SNARE zipping.

SNAP-25 (synaptosome-associated protein of 25,000 daltons) is a membrane bound protein anchored to the cytosolic face of membranes via palmitoyl side chains in the middle of the molecule. SNAP-25 is Q-SNARE protein contributing two α-helices in the formation of the exocytotic fusion complex in neurons where it assembles with syntaxin-1 and synaptobrevin. SNAP-25 inhibits P/Q- and L-type voltage-gated calcium channels located presynaptically ^[1] and interacts with the synaptotagmin C2B domain in Ca²⁺-independent fashion ^[2]. In glutamatergic synapses SNAP-25 decreases the Ca²⁺ responsiveness, while it is naturally absent in GABAergic synapses ^[3].

Consistent with the regulation of synaptic Ca²⁺ responsiveness, heterozygous deletion of the SNAP-25 gene in mice results in a hyperactive phenotype similar to attention deficit hyperactivity disorder (ADHD). In heterozygous mice, a decrease in hyperactivity is observed with dextroamphetamine, the active ingredient of the ADHD drug Adderall®. Homozygous deletions of the SNAP-25 gene are lethal. Subsequent studies have suggested that at least some of the SNAP-25 gene mutations in humans might predispose to ADHD ^[4]^[5].

Botulinum toxins A and E cleave SNAP-25 ^[6] leading to paralysis in clinically developed botulism.

[edit] References

^ Hodel A (1998). "SNAP-25". The International Journal of Biochemistry & Cell Biology 30 (10): 1069-1073.
^ Chapman ER (2002). "Synaptotagmin: A Ca²⁺ sensor that triggers exocytosis?". Nature Reviews Molecular Cell Biology 3: 498-508.
^ Pozzi D, Verderio C, Patti L, Grumelli C, Inverardi F, Frassoni C, Bonanno G, Matteoli M (2004). "SNAP-25 modulation of calcium dynamics underlies differences in GABAergic and glutamatergic responsiveness to depolarization". Neuron 41 (4): 599-610.
^ Brophy K, Hawi Z, Kirley A, Fitzgerald M, Gill M (2002). "Synaptosomal-associated protein 25 (SNAP-25) and attention deficit hyperactivity disorder (ADHD): evidence of linkage and association in the Irish population". Molecular Psychiatry 7 (8): 913-917.
^ Mill J, Curran S, Kent L, Gould A, Huckett L, Richards S, Taylor E, Asherson P (2002). "Association study of a SNAP-25 microsatellite and attention deficit hyperactivity disorder". American Journal of Medical Genetics 114 (3): 269-271.
^ Aoki KR, Guyer B (2001). "Botulinum toxin type A and other botulinum toxin serotypes: a comparative review of biochemical and pharmacological actions". European Journal of Neurology 8: 21-29.