Modulation of neurotransmission by GPCRs is dependent upon the microarchitecture of the primed vesicle complex.
J Neurosci
; 34(1): 260-74, 2014 Jan 01.
Article
em En
| MEDLINE
| ID: mdl-24381287
ABSTRACT
G(i/o)-protein-coupled receptors (GPCRs) ubiquitously inhibit neurotransmission, principally via Gßγ, which acts via a number of possible effectors. GPCR effector specificity has traditionally been attributed to Gα, based on Gα's preferential effector targeting in vitro compared with Gßγ's promiscuous targeting of various effectors. In synapses, however, Gßγ clearly targets unique effectors in a receptor-dependent way to modulate synaptic transmission. It remains unknown whether Gßγ specificity in vivo is due to specific Gßγ isoform-receptor associations or to spatial separation of distinct Gßγ pathways through macromolecular interactions. We thus sought to determine how Gßγ signaling pathways within axons remain distinct from one another. In rat hippocampal CA1 axons, GABA(B) receptors (GABA(B)Rs) inhibit presynaptic Ca(2+) entry, and we have now demonstrated that 5-HT(1B) receptors (5-HT(1B)Rs) liberate Gßγ to interact with SNARE complex C terminals with no effect on Ca(2+) entry. Both GABA(B)Rs and 5-HT(1B)Rs inhibit Ca(2+)-evoked neurotransmitter release, but 5-HT(1B)Rs have no effect on Sr(2+)-evoked release. Sr(2+), unlike Ca(2+), does not cause synaptotagmin to compete with Gßγ binding to SNARE complexes. 5-HT(1B)Rs also fail to inhibit release following cleavage of the C terminus of the SNARE complex protein SNAP-25 with botulinum A toxin. Thus, GABA(B)Rs and 5-HT(1B)Rs both localize to presynaptic terminals, but target distinct effectors. We demonstrate that disruption of SNARE complexes and vesicle priming with botulinum C toxin eliminates this selectivity, allowing 5-HT(1B)R inhibition of Ca(2+) entry. We conclude that receptor-effector specificity requires a microarchitecture provided by the SNARE complex during vesicle priming.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Transmissão Sináptica
/
Receptores Acoplados a Proteínas G
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Proteínas SNARE
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Hipocampo
Limite:
Animals
Idioma:
En
Revista:
J Neurosci
Ano de publicação:
2014
Tipo de documento:
Article