title: Synaptic Zn2+ inhibits neurotransmitter release by promoting endocannabinoid synthesis.
abstract: Although it is well established that many glutamatergic neurons sequester Zn(2+) within their synaptic vesicles, the physiological significance of synaptic Zn(2+) remains poorly understood. In experiments performed in a Zn(2+)-enriched auditory brainstem nucleus--the dorsal cochlear nucleus--we discovered that synaptic Zn(2+) and GPR39, a putative metabotropic Zn(2+)-sensing receptor (mZnR), are necessary for triggering the synthesis of the endocannabinoid 2-arachidonoylglycerol (2-AG). The postsynaptic production of 2-AG, in turn, inhibits presynaptic probability of neurotransmitter release, thus shaping synaptic strength and short-term synaptic plasticity. Zn(2+)-induced inhibition of transmitter release is absent in mutant mice that lack either vesicular Zn(2+) or the mZnR. Moreover, mass spectrometry measurements of 2-AG levels reveal that Zn(2+)-mediated initiation of 2-AG synthesis is absent in mice lacking the mZnR. We reveal a previously unknown action of synaptic Zn(2+): synaptic Zn(2+) inhibits glutamate release by promoting 2-AG synthesis.
authors.affiliation: Department of Otolaryngology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261, USA.
authors.forename: Tamara
authors.initials: T
authors.lastname: Perez-Rosello
authors.forename: Charles T
authors.initials: CT
authors.lastname: Anderson
authors.forename: Francisco J
authors.initials: FJ
authors.lastname: Schopfer
authors.forename: Yanjun
authors.initials: Y
authors.lastname: Zhao
authors.forename: David
authors.initials: D
authors.lastname: Gilad
authors.forename: Sonia R
authors.initials: SR
authors.lastname: Salvatore
authors.forename: Bruce A
authors.initials: BA
authors.lastname: Freeman
authors.forename: Michal
authors.initials: M
authors.lastname: Hershfinkel
authors.forename: Elias
authors.initials: E
authors.lastname: Aizenman
authors.forename: Thanos
authors.initials: T
authors.lastname: Tzounopoulos
mesh_terms: D000818:Animals; D001095:Arachidonic Acids / Q000378:metabolism; D002853:Chromatography, Liquid; D003712:Dendrites / Q000502:physiology; D063388:Endocannabinoids / Q000096:biosynthesis* / Q000378:metabolism; D005260:Female; D018698:Glutamic Acid / Q000378:metabolism; D005989:Glycerides / Q000378:metabolism; D008297:Male; D013058:Mass Spectrometry; D051379:Mice; D008813:Mice, Inbred ICR; D018345:Mice, Knockout; D008856:Microscopy, Fluorescence; D009412:Nerve Fibers / Q000502:physiology; D018377:Neurotransmitter Agents / Q000378:metabolism*; D018408:Patch-Clamp Techniques; D015398:Signal Transduction / Q000502:physiology; D013569:Synapses / Q000502:physiology*; D009435:Synaptic Transmission / Q000502:physiology; D015032:Zinc / Q000502:physiology*
chemical_list: D001095:Arachidonic Acids; D063388:Endocannabinoids; D005989:Glycerides; D018377:Neurotransmitter Agents; D018698:Glutamic Acid; C094503:glyceryl 2-arachidonate; D015032:Zinc