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![Activation of presynaptic Gi/o-coupled receptors by hormones, neurotransmitters (NT) and neuromodulators leads to decreased neurotransmission. This decreased release provides an important control mechanism for autoreceptors to guard against over-activation, and an important homeostatic mechanism. For heteroreceptors, it is a critical component of synaptic integration mediating circuitry-level effects. Fast membrane-delimited inhibition of secretion may occur via Gβγ regulation of voltage-dependent Ca2+channels (VDCCs). However, a direct interaction between Gβγ and soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) proteins also leads to inhibition of exocytosis downstream of Ca2+ entry [1]. This mechanism is not only more acute and direct in controlling evoked release, leaving secondary effects of presynaptic Ca2+ unaffected, but is also able to modify components of exocytosis not available to mechanisms that control release probability. These include modifying the concentration of neurotransmitter released [2] by interacting with a region of the SNARE complex that controls fusion rate, but also modifying spontaneous release, which has important roles in its own right. The same synapses can have different Gi/o-GPCR-triggered modulation of neurotransmitter release by different mechanisms. For example, in hippocampal neurons, GABAB receptors cause decreased Ca2+ entry and 5HT1b receptors inhibit exocytosis by directly acting on SNAREs at the same synapse: this allows for presynaptic neural integration [3]. What could be the mechanistic basis of this specificity? There is considerable evidence that unique Gβγ isoforms play specific roles in mediating interactions with both receptors and effectors. Our recent _in vivo_ proteomic studies of Gβγ specificity suggest that it might come from receptor selection of particular Gβγ subunits [4], and the affinity of those Gβγ‘s for the SNARE complex (unpublished). Understanding of the physiological role of Gβγ-SNARE interaction has lagged because of a lack of tools. But recent progress in understanding the molecular basis of this interaction, in particular a target for Gβγ at the C-terminal of SNAP25 [5] has yielded a transgenic SNAP25Δ3 mouse with a selectively disturbed Gβγ–SNARE interaction. This mouse has normal evoked exocytosis and normal GABAergic inhibition of VDCC, but disturbed inhibition of exocytosis through Gβγ–SNARE interaction. The SNAP25Δ3 mouse provides clear evidence that the Gβγ–SNARE locus is physiologically important for regulation, because it has a number of interesting phenotypes both central and peripheral, including elevated stress-induced hyperthermia, impaired supraspinal nociception, defective spatial learning, impaired gait, and depressive-like behavior [6]. Most interestingly, the two Gβγ-mediated inhibitory mechanisms, co-occurring at the same synapse, are synergistic with each other: a completely unexpected result. This observation suggests that combinations of neurotransmitters may shape neuromodulation, potentially giving rise to novel effects on circuits. Thus, synaptic integration can occur as much presynaptically as postsynaptically. The specificity of the two mechanisms raises the possibility that targeting the Gβγ-SNARE interaction may be a therapeutic strategy, and, further, that therapeutic pairing of drugs that affect each mechanism may themselves work synergistically, an exciting possibility. FUNDING AND DISCLOSURE Funding for this study was provided by the NIMH, R01 MH084874, R01 MH064763, and R01 MH101679, NINDS, R01 NS111749, R01 NS052699, and NIDDK, R01 DK109204. REFERENCES * Blackmer T, Larsen EC, Takahashi M, Martin TF, Alford S, Hamm HE. G protein βγ subunit-mediated presynaptic inhibition: regulation of exocytotic fusion downstream of Ca2+ entry. Science. 2001;292:293–297. Article CAS Google Scholar * Photowala H, Blackmer T, Schwartz E, Hamm HE, Alford S. G protein βγsubunits activated by serotonin mediate presynaptic inhibition by regulating vesicle fusion properties. Proc Natl Acad Sci USA. 2006;103:4281–4286. Article CAS Google Scholar * Hamid E, Church E, Wells CA, Zurawski Z, Hamm HE, Alford S. Modulation of neurotransmission by GPCRs is dependent upon the microarchitecture of the primed vesicle complex. J Neurosci. 2014;34:260–274. Article CAS Google Scholar * Yim YY, Betke KM, McDonald WH, Gilsbach R, Chen Y, Hyde K, Wang Q, Hein L, Hamm HE. The in vivo specificity of synaptic G β and G γ subunits to the alpha2a adrenergic receptor at CNS synapses. Sci Rep. 2019;9:1718. Article Google Scholar * Gerachshenko T, Blackmer T, Yoon E-J, Bartleson C, Hamm HE, Alford S. G βγ acts at the C terminus of SNAP-25 to mediate presynaptic inhibition. Nat Neurosci. 2005;8:597–605. Article CAS Google Scholar * Zurawski Z, Thompson Gray AD, Brady LJ, Page B, Church E, Harris NA, Dohn MR, Yim YY, Hyde K, Mortlock DP, Jones CK, Winder DG, Alford S, Hamm HE. Disabling the G βγ-SNARE interaction disrupts GPCR-mediated presynaptic inhibition, leading to physiological and behavioral phenotypes. Sci Signal. 2019;12:pii: eaat8595. Article Google Scholar Download references ACKNOWLEDGEMENTS We owe a debt of gratitude to the many research collaborators, students and postdoctoral fellows that have contributed to this project. Prior researchers include T Blackmer who started these studies, E-J Yoon, T Gerachshenko, and E Hamid. More recent contributors include Z Zurawski, A Thompson Gray, Y-Y Yim, L Brady, B Page, E Church, S Rodriguez, N Harris, M Dohn, K Hyde, D Mortlock, C Jones, and D Winder. We thank all of these scientists for their collaboration, discussions, inspiration and support. AUTHOR INFORMATION AUTHORS AND AFFILIATIONS * Aileen M. Lange and Annie Mary Lyle Chair in Cardiovascular Research, Department of Pharmacology, Vanderbilt University, Nashville, TN, 37212, USA Heidi E. Hamm * Sweeney Professor of Basic Sciences and Head, Department of Anatomy and Cell Biology, University of Illinois at Chicago, College of Medicine, 808S. Wood St., Chicago, IL, 60612, USA Simon T. Alford Authors * Heidi E. Hamm View author publications You can also search for this author inPubMed Google Scholar * Simon T. Alford View author publications You can also search for this author inPubMed Google Scholar CORRESPONDING AUTHORS Correspondence to Heidi E. Hamm or Simon T. Alford. ETHICS DECLARATIONS COMPETING INTERESTS The authors declare no competing interests. ADDITIONAL INFORMATION PUBLISHER’S NOTE: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. RIGHTS AND PERMISSIONS Reprints and permissions ABOUT THIS ARTICLE CITE THIS ARTICLE Hamm, H.E., Alford, S.T. Physiological roles for neuromodulation via Gi/o GPCRs working through Gβγ–SNARE interaction. _Neuropsychopharmacol._ 45, 221 (2020). https://doi.org/10.1038/s41386-019-0497-2 Download citation * Published: 02 September 2019 * Issue Date: January 2020 * DOI: https://doi.org/10.1038/s41386-019-0497-2 SHARE THIS ARTICLE Anyone you share the following link with will be able to read this content: Get shareable link Sorry, a shareable link is not currently available for this article. 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Activation of presynaptic Gi/o-coupled receptors by hormones, neurotransmitters (NT) and neuromodulators leads to decreased neurotransmission. This decreased release provides an important
control mechanism for autoreceptors to guard against over-activation, and an important homeostatic mechanism. For heteroreceptors, it is a critical component of synaptic integration
mediating circuitry-level effects. Fast membrane-delimited inhibition of secretion may occur via Gβγ regulation of voltage-dependent Ca2+channels (VDCCs). However, a direct interaction
between Gβγ and soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) proteins also leads to inhibition of exocytosis downstream of Ca2+ entry [1]. This mechanism is
not only more acute and direct in controlling evoked release, leaving secondary effects of presynaptic Ca2+ unaffected, but is also able to modify components of exocytosis not available to
mechanisms that control release probability. These include modifying the concentration of neurotransmitter released [2] by interacting with a region of the SNARE complex that controls fusion
rate, but also modifying spontaneous release, which has important roles in its own right. The same synapses can have different Gi/o-GPCR-triggered modulation of neurotransmitter release by
different mechanisms. For example, in hippocampal neurons, GABAB receptors cause decreased Ca2+ entry and 5HT1b receptors inhibit exocytosis by directly acting on SNAREs at the same synapse:
this allows for presynaptic neural integration [3]. What could be the mechanistic basis of this specificity? There is considerable evidence that unique Gβγ isoforms play specific roles in
mediating interactions with both receptors and effectors. Our recent _in vivo_ proteomic studies of Gβγ specificity suggest that it might come from receptor selection of particular Gβγ
subunits [4], and the affinity of those Gβγ‘s for the SNARE complex (unpublished). Understanding of the physiological role of Gβγ-SNARE interaction has lagged because of a lack of tools. But
recent progress in understanding the molecular basis of this interaction, in particular a target for Gβγ at the C-terminal of SNAP25 [5] has yielded a transgenic SNAP25Δ3 mouse with a
selectively disturbed Gβγ–SNARE interaction. This mouse has normal evoked exocytosis and normal GABAergic inhibition of VDCC, but disturbed inhibition of exocytosis through Gβγ–SNARE
interaction. The SNAP25Δ3 mouse provides clear evidence that the Gβγ–SNARE locus is physiologically important for regulation, because it has a number of interesting phenotypes both central
and peripheral, including elevated stress-induced hyperthermia, impaired supraspinal nociception, defective spatial learning, impaired gait, and depressive-like behavior [6]. Most
interestingly, the two Gβγ-mediated inhibitory mechanisms, co-occurring at the same synapse, are synergistic with each other: a completely unexpected result. This observation suggests that
combinations of neurotransmitters may shape neuromodulation, potentially giving rise to novel effects on circuits. Thus, synaptic integration can occur as much presynaptically as
postsynaptically. The specificity of the two mechanisms raises the possibility that targeting the Gβγ-SNARE interaction may be a therapeutic strategy, and, further, that therapeutic pairing
of drugs that affect each mechanism may themselves work synergistically, an exciting possibility. FUNDING AND DISCLOSURE Funding for this study was provided by the NIMH, R01 MH084874, R01
MH064763, and R01 MH101679, NINDS, R01 NS111749, R01 NS052699, and NIDDK, R01 DK109204. REFERENCES * Blackmer T, Larsen EC, Takahashi M, Martin TF, Alford S, Hamm HE. G protein βγ
subunit-mediated presynaptic inhibition: regulation of exocytotic fusion downstream of Ca2+ entry. Science. 2001;292:293–297. Article CAS Google Scholar * Photowala H, Blackmer T,
Schwartz E, Hamm HE, Alford S. G protein βγsubunits activated by serotonin mediate presynaptic inhibition by regulating vesicle fusion properties. Proc Natl Acad Sci USA. 2006;103:4281–4286.
Article CAS Google Scholar * Hamid E, Church E, Wells CA, Zurawski Z, Hamm HE, Alford S. Modulation of neurotransmission by GPCRs is dependent upon the microarchitecture of the primed
vesicle complex. J Neurosci. 2014;34:260–274. Article CAS Google Scholar * Yim YY, Betke KM, McDonald WH, Gilsbach R, Chen Y, Hyde K, Wang Q, Hein L, Hamm HE. The in vivo specificity of
synaptic G β and G γ subunits to the alpha2a adrenergic receptor at CNS synapses. Sci Rep. 2019;9:1718. Article Google Scholar * Gerachshenko T, Blackmer T, Yoon E-J, Bartleson C, Hamm HE,
Alford S. G βγ acts at the C terminus of SNAP-25 to mediate presynaptic inhibition. Nat Neurosci. 2005;8:597–605. Article CAS Google Scholar * Zurawski Z, Thompson Gray AD, Brady LJ,
Page B, Church E, Harris NA, Dohn MR, Yim YY, Hyde K, Mortlock DP, Jones CK, Winder DG, Alford S, Hamm HE. Disabling the G βγ-SNARE interaction disrupts GPCR-mediated presynaptic inhibition,
leading to physiological and behavioral phenotypes. Sci Signal. 2019;12:pii: eaat8595. Article Google Scholar Download references ACKNOWLEDGEMENTS We owe a debt of gratitude to the many
research collaborators, students and postdoctoral fellows that have contributed to this project. Prior researchers include T Blackmer who started these studies, E-J Yoon, T Gerachshenko, and
E Hamid. More recent contributors include Z Zurawski, A Thompson Gray, Y-Y Yim, L Brady, B Page, E Church, S Rodriguez, N Harris, M Dohn, K Hyde, D Mortlock, C Jones, and D Winder. We thank
all of these scientists for their collaboration, discussions, inspiration and support. AUTHOR INFORMATION AUTHORS AND AFFILIATIONS * Aileen M. Lange and Annie Mary Lyle Chair in
Cardiovascular Research, Department of Pharmacology, Vanderbilt University, Nashville, TN, 37212, USA Heidi E. Hamm * Sweeney Professor of Basic Sciences and Head, Department of Anatomy and
Cell Biology, University of Illinois at Chicago, College of Medicine, 808S. Wood St., Chicago, IL, 60612, USA Simon T. Alford Authors * Heidi E. Hamm View author publications You can also
search for this author inPubMed Google Scholar * Simon T. Alford View author publications You can also search for this author inPubMed Google Scholar CORRESPONDING AUTHORS Correspondence to
Heidi E. Hamm or Simon T. Alford. ETHICS DECLARATIONS COMPETING INTERESTS The authors declare no competing interests. ADDITIONAL INFORMATION PUBLISHER’S NOTE: Springer Nature remains neutral
with regard to jurisdictional claims in published maps and institutional affiliations. RIGHTS AND PERMISSIONS Reprints and permissions ABOUT THIS ARTICLE CITE THIS ARTICLE Hamm, H.E.,
Alford, S.T. Physiological roles for neuromodulation via Gi/o GPCRs working through Gβγ–SNARE interaction. _Neuropsychopharmacol._ 45, 221 (2020). https://doi.org/10.1038/s41386-019-0497-2
Download citation * Published: 02 September 2019 * Issue Date: January 2020 * DOI: https://doi.org/10.1038/s41386-019-0497-2 SHARE THIS ARTICLE Anyone you share the following link with will
be able to read this content: Get shareable link Sorry, a shareable link is not currently available for this article. Copy to clipboard Provided by the Springer Nature SharedIt
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