GPCR mediated regulation of synaptic transmission

doi:10.1016/j.pneurobio.2012.01.009

Progress in Neurobiology

Volume 96, Issue 3, March 2012, Pages 304-321

https://doi.org/10.1016/j.pneurobio.2012.01.009 Get rights and content

Abstract

Synaptic transmission is a finely regulated mechanism of neuronal communication. The release of neurotransmitter at the synapse is not only the reflection of membrane depolarization events, but rather, is the summation of interactions between ion channels, G protein coupled receptors, second messengers, and the exocytotic machinery itself which exposes the components within a synaptic vesicle to the synaptic cleft. The focus of this review is to explore the role of G protein signaling as it relates to neurotransmission, as well as to discuss the recently determined inhibitory mechanism of Gβγ dimers acting directly on the exocytotic machinery proteins to inhibit neurotransmitter release.

Highlights

► This review focuses on the presynaptic regulation of neurotransmission. ► Heterotrimeric G protein signaling is an important part of that regulation. ► Gβγ has a novel means of regulating synaptic neurotransmission. ► This regulation may have a large impact on disease pathology and treatment. ► There are many open questions relating to G protein signaling and neurotransmission.

Introduction

Efficient communication between neurons in the brain is crucial to the normal functioning of the nervous system as it ensures integration of both external and internal sensory input, and permits the generation of appropriate behaviors to meet the demands of an individual's environment (Goodman et al., 2001). As a result, understanding the process of synaptic transmission is essential to understanding how normal processes are coordinated, but also how they may be disrupted by injury and disease. In its most elementary form, synaptic transmission is simply the communication between one presynaptic neuron and a single postsynaptic cell as well as the processing by the postsynaptic cell of the signal that it receives (Kandel et al., 2000). At chemical synapses, signal transduction is achieved by the rapid conversion of an arriving electrical signal into a chemical one that diffuses between the cells (Schoch and Gundelfinger, 2006, Zhai and Bellen, 2004). Structurally, these complex, asymmetrical cell–cell contact sites are formed from the axon terminal membrane of the presynaptic neuron, juxtaposed with the postsynaptic density on the postsynaptic cell (Dresbach et al., 2001, Schoch and Gundelfinger, 2006).

Membrane depolarization caused by the arrival of presynaptic action potentials induces the opening of voltage-dependent calcium channels (VDCC), with the resulting calcium transient stimulating synaptic vesicle exocytosis from the active zone of the presynaptic terminal (Sudhof, 2004). Such regulated exocytosis releases neurotransmitter into the synaptic cleft whereupon it activates receptors or channels on the postsynaptic membrane to ensure continued propagation of the signal (Dresbach et al., 2001, Sudhof, 2004). When these chemical synapses are examined, two distinct types of vesicles are evident: small, clear synaptic vesicles which are filled with classical neurotransmitters such as acetylcholine, glutamate, and the monoamines, and large dense-core vesicles filled with neuropeptides and neurohormones. While these vesicles differ in their morphology, release kinetics, and distribution, they maintain conserved machinery for fusion events, and both exhibit calcium-dependence for exocytosis (Park and Kim, 2009).

Released neurotransmitters bind to ligand-gated ion channels on postsynaptic neurons to mediate voltage changes in the postsynaptic cell. Major modulators of neurotransmitter action are G protein coupled receptors (GPCRs). These seven membrane-spanning α-helical proteins bind specifically to their respective neurotransmitters, causing a change in the structure of the receptor, and resulting in activation of heterotrimeric guanine–nucleotide binding proteins. G_i/o-coupled autoreceptors on both pre- and postsynaptic cells guard against overstimulation by release of G protein βγ subunits which postsynaptically activate G protein-coupled inward rectifier K+ (GIRK) channels and presynaptically inhibit voltage activated calcium channels (Kajikawa et al., 2001, Takahashi et al., 1996). Gβγ subunits can also directly interact with the vesicle exocytotic machinery, soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) proteins (Blackmer et al., 2001, Delaney et al., 2007, Gerachshenko et al., 2005). G_i/o-coupled heteroreceptors mediate circuit-level modulation of neurotransmitter responses.

The goal of this review is to discuss the regulation of exocytosis at the synapse by G protein coupled receptor signaling pathways with a focus on the role and mechanism of Gβγ signaling and the novel direct modulation on the exocytotic machinery.

Section snippets

Regulatory components controlling vesicle docking, priming, and exocytosis at the presynaptic membrane

The short latency between calcium influx at a presynaptic terminal and the release of neurotransmitter suggests that a population of vesicles sits poised to fuse with the plasma membrane immediately following calcium entry (Katz, 1969, Weimer and Richmond, 2005). To achieve such temporal precision, vesicles undergo a series of maturation steps at the presynaptic membrane known as docking and priming, in order to become fusion competent (see Fig. 1). Docked vesicles were traditionally defined

G protein coupled receptors

GPCRs are a large superfamily of proteins which convey the majority of signal transduction across cell membranes and mediate a vast array of cellular responses necessary for the normal physiology of the body (Eglen and Reisine, 2009, Millar and Newton, 2010, Oldham and Hamm, 2008). Encoded by nearly 800 different genes in humans, these proteins are activated by a wide variety of ligands ranging from single photons, odorants, and amino acids to hormones, neurotransmitters, and proteolytic

Implications of G protein modulation of synaptic transmission for disease

As many G_i/o-coupled GPCRs act as feedback regulators for transmitter release from presynaptic terminals, a greater understanding of the mechanisms by which they operate will be important for understanding normal neural processing, but also because dysregulation of this process can have serious health consequences. For example, mutations in the promoter of the 5HT_1a serotonin receptor results in abnormally high autoreceptor expression, decreased serotonin release, and increased susceptibility

Open questions

A number of open questions remain regarding the role Gβγ–SNARE interactions play in regulating exocytosis. For example, what is the role of individual Gβγ isoforms in this process? Despite the 5 Gβ and 13 Gγ subunits sharing high levels of sequence identity (Downes and Gautam, 1999, Hildebrandt, 1997), it is known that pairs can exhibit functional selectivity in their interactions with both receptors and effectors (Dingus et al., 2005, Kleuss et al., 1993, Richardson and Robishaw, 1999).

Conclusion

GPCR mediated regulation of synaptic transmission is complex and transcends many different pathways. While a great deal has been learned to date, numerous questions still remain as to the mechanisms underlying this process in the brain as well as other systems. While interactions between Gβγ subunits and classical effectors are well established, newer mechanisms such as Gβγ–SNARE interactions highlight levels of intricacy as yet unknown. Further research into this novel protein–protein

Acknowledgement

Research in the authors’ laboratory was supported by a grant from the National Institute of Health, R01 EY010291.

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GPCR mediated regulation of synaptic transmission

Abstract

Highlights

Introduction

Section snippets

Regulatory components controlling vesicle docking, priming, and exocytosis at the presynaptic membrane

G protein coupled receptors

Implications of G protein modulation of synaptic transmission for disease

Open questions

Conclusion

Acknowledgement

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Blood

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Neuroscience

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Cell. Signal.

Neuron

Genomics

Neuron

Neuron

Biochem. Biophys. Res. Commun.

J. Biol. Chem.

Cell. Signal.

Cell

J. Biol. Chem.

Blood

J. Biol. Chem.

Biochem. Pharmacol.

Curr. Biol.

Biochim. Biophys. Acta

Neuron

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Biochemistry

Evaluation of autoreceptor-mediated control of [3H]acetylcholine release in rat and human neocortex

Exp. Brain Res.

M2 muscarinic receptor-mediated inhibition of the Ca2+ current in rat magnocellular cholinergic basal forebrain neurones

J. Physiol.

Drosophila Unc-13 is essential for synaptic transmission

Nat. Neurosci.

Dopamine D1 receptor mechanisms in the cognitive performance of young adult and aged monkeys

Psychopharmacology (Berl.)

Munc13-1 is essential for fusion competence of glutamatergic synaptic vesicles

Nature

Neurotransmitter inhibition of neuronal calcium currents by changes in channel voltage dependence

Nature

Vesicle pools, docking, priming, and release

Cell Tissue Res.

Presynaptic depression of excitatory synaptic inputs to rat hypoglossal motoneurons by muscarinic M2 receptors

J. Neurophysiol.

Syntaxin: a synaptic protein implicated in docking of synaptic vesicles at presynaptic active zones

Science

Molecular determinants of the functional interaction between syntaxin and N-type Ca2+ channel gating

Proc. Natl. Acad. Sci. U. S. A.

G protein betagamma subunit-mediated presynaptic inhibition: regulation of exocytotic fusion downstream of Ca2+ entry

Science

G protein betagamma directly regulates SNARE protein fusion machinery for secretory granule exocytosis

Nat. Neurosci.

Presynaptic alpha2-adrenoceptors control excitatory, but not inhibitory, transmission at rat hippocampal synapses

J. Physiol.

Modulation of N-type calcium channels in bullfrog sympathetic neurons by luteinizing hormone-releasing hormone: kinetics and voltage dependence

J. Neurosci.

Tonic dopaminergic stimulation impairs associative learning in healthy subjects

Neuropsychopharmacology

Synaptotagmin – a calcium sensor on the synaptic vesicle surface

Science

Presynaptic signaling by heterotrimeric G-proteins

Handb. Exp. Pharmacol.

Endocannabinoids inhibit transmission at granule cell to Purkinje cell synapses by modulating three types of presynaptic calcium channels

J. Neurosci.

Ca²⁺-stimulated catecholamine release from alpha-toxin-permeabilized PC12 cells: biochemical evidence for exocytosis and its modulation by protein kinase C and G proteins

M2 muscarinic receptor-mediated inhibition of the Ca²⁺ current in rat magnocellular cholinergic basal forebrain neurones

Molecular determinants of the functional interaction between syntaxin and N-type Ca²⁺ channel gating

G protein betagamma subunit-mediated presynaptic inhibition: regulation of exocytotic fusion downstream of Ca²⁺ entry