Depolarization by K+ and glutamate activates different neurotransmitter release mechanisms in gabaergic neurons: Vesicular versus non-vesicular release of GABA

Synapses are highly specialized intercellular junctions organized by adhesive and scaffolding molecules that align presynaptic vesicular release with postsynaptic neurotransmitter receptors. The MALS/Veli–CASK–Mint-1 complex of PDZ proteins occurs on both sides of the synapse and has the potential to link transsynaptic adhesion molecules to the cytoskeleton. In this study, we purified the MALS protein complex from brain and found liprin-α as a major component. Liprin proteins organize the presynaptic active zone and regulate neurotransmitter release. Fittingly, mutant mice lacking all three MALS isoforms died perinatally with difficulty breathing and impaired excitatory synaptic transmission. Excitatory postsynaptic currents were dramatically reduced in autaptic cultures from MALS triple knockout mice due to a presynaptic deficit in vesicle cycling. These findings are consistent with a model whereby the MALS–CASK–liprin-α complex recruits components of the synaptic release machinery to adhesive proteins of the active zone.

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Reexamination of N-terminal domains of Syntaxin-1 in vesicle fusion from central murine synapses

eLife ◽

10.7554/elife.69498 ◽

2021 ◽

Vol 10 ◽

Author(s):

Gülçin Vardar ◽

Andrea Salazar-Lázaro ◽

Marisa M Brockmann ◽

Marion Weber-Boyvat ◽

Sina Zobel ◽

...

Keyword(s):

Synaptic Transmission ◽

Neurotransmitter Release ◽

Null Mouse ◽

General View ◽

Binding Modes ◽

Short Term ◽

Short Term Plasticity ◽

Open Conformation ◽

Vesicular Release ◽

Mouse Model System

Syntaxin-1 (STX1) and Munc18-1 are two requisite components of synaptic vesicular release machinery, so much so synaptic transmission cannot proceed in their absence. They form a tight complex through two major binding modes: through STX1's N-peptide and through STX's closed conformation driven by its Habc- domain. However, physiological roles of these two reportedly different binding modes in synapses are still controversial. Here we characterized the roles of STX1's N-peptide, Habc-domain, and open conformation with and without N-peptide deletion using our STX1-null mouse model system and exogenous reintroduction of STX1A mutants. We show, on the contrary to the general view, that the Habc-domain is absolutely required and N-peptide is dispensable for synaptic transmission. However, STX1A's N-peptide plays a regulatory role, particularly in the Ca2+-sensitivity and the short-term plasticity of vesicular release, whereas STX1's open-conformation governs the vesicle fusogenicity. Strikingly, we also show neurotransmitter release still proceeds when the two interaction modes between STX1A and Munc18-1 are presumably intervened, necessitating a refinement of the conceptualization of STX1A-Munc18-1 interaction.

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Functions of Presynaptic Voltage-gated Calcium Channels

Function ◽

10.1093/function/zqaa027 ◽

2020 ◽

Vol 2 (1) ◽

Author(s):

Annette C Dolphin

Keyword(s):

Calcium Channels ◽

Neurotransmitter Release ◽

Action Potentials ◽

Voltage Dependence ◽

Kinetic Properties ◽

Excitable Cells ◽

Single Action ◽

Voltage Gated ◽

Voltage Gated Calcium Channels ◽

Vesicular Release

Abstract Voltage-gated calcium channels are the principal conduits for depolarization-mediated Ca2+ entry into excitable cells. In this review, the biophysical properties of the relevant members of this family of channels, those that are present in presynaptic terminals, will be discussed in relation to their function in mediating neurotransmitter release. Voltage-gated calcium channels have properties that ensure they are specialized for particular roles, for example, differences in their activation voltage threshold, their various kinetic properties, and their voltage-dependence of inactivation. All these attributes play into the ability of the various voltage-gated calcium channels to participate in different patterns of presynaptic vesicular release. These include synaptic transmission resulting from single action potentials, and longer-term changes mediated by bursts or trains of action potentials, as well as release resulting from graded changes in membrane potential in specialized sensory synapses.

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Glutamatergic and GABAergic neurons mediate distinct neurodevelopmental phenotypes of STXBP1 encephalopathy

10.1101/2021.07.13.452234 ◽

2021 ◽

Author(s):

Joo Hyun Kim ◽

Wu Chen ◽

Eugene S Chao ◽

Hongmei Chen ◽

Mingshan Xue

Keyword(s):

Broad Spectrum ◽

Neurotransmitter Release ◽

Gabaergic Neurons ◽

Disease Mechanism ◽

Gabaergic Neurotransmission ◽

Epileptic Encephalopathies ◽

Disease Phenotypes ◽

Pathogenic Variants ◽

Distinct Disease ◽

Inhibitory Signaling

Heterozygous pathogenic variants in syntaxin-binding protein 1 (STXBP1, also known as MUNC18-1) cause STXBP1 encephalopathy and are among the most frequent causes of developmental and epileptic encephalopathies and intellectual disabilities. STXBP1 is an essential protein for presynaptic neurotransmitter release, and its haploinsufficiency impairs glutamatergic and GABAergic neurotransmission. However, the mechanism underlying the broad spectrum of neurological phenotypes is poorly understood. Here we show that glutamatergic and GABAergic neurons mediate distinct disease features with few overlaps. Glutamatergic and GABAergic neurons-specific Stxbp1 haploinsufficient mice exhibit different subsets of the cognitive and seizure phenotypes observed in the constitutive Stxbp1 haploinsufficient mice. Developmental delay and most of the motor and psychiatric phenotypes are only recapitulated by GABAergic Stxbp1 haploinsufficiency. Thus, the contrasting roles of excitatory and inhibitory signaling in STXBP1 encephalopathy identify GABAergic dysfunction as a main disease mechanism and reveal the possibility to selectively modulate disease phenotypes by targeting specific neurotransmitter systems.

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