Exocytosis Proteins: Typical and Atypical Mechanisms of Action in Skeletal Muscle

Hwang, Jin-Hee; Thurmond, Debbie C.

doi:10.3389/fendo.2022.915509

Cited by 3 publications

(1 citation statement)

References 236 publications

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“…GPCR-and SNARE-dependent signals are involved in regulating metabolically important activities, such as feeding behavior, energy balance, insulin secretion, and thermoregulation (19)(20)(21). However, the specific roles that Gβγ-dependent signals play in regulating these physiologic responses are unknown.…”

Section: Introductionmentioning

confidence: 99%

Gβγ-SNAP25 exocytotic brake removal enhances insulin action, promotes adipocyte browning, and protects against diet-induced obesity

Ceddia¹,

Zurawski²,

Gray³

et al. 2023

Journal of Clinical Investigation

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Negative regulation of exocytosis from secretory cells is accomplished through inhibitory signals from G i/o GPCRs by Gβγ subunit inhibition of 2 mechanisms: decreased calcium entry and direct interaction of Gβγ with soluble N -ethylmaleimide–sensitive factor attachment protein (SNAP) receptor (SNARE) plasma membrane fusion machinery. Previously, we disabled the second mechanism with a SNAP25 truncation (SNAP25Δ3) that decreased Gβγ affinity for the SNARE complex, leaving exocytotic fusion and modulation of calcium entry intact and removing GPCR-Gβγ inhibition of SNARE-mediated exocytosis. Here, we report substantial metabolic benefit in mice carrying this mutation. Snap25 Δ3/Δ3 mice exhibited enhanced insulin sensitivity and beiging of white fat. Metabolic protection was amplified in Snap25 Δ3/Δ3 mice challenged with a high-fat diet. Glucose homeostasis, whole-body insulin action, and insulin-mediated glucose uptake into white adipose tissue were improved along with resistance to diet-induced obesity. Metabolic protection in Snap25 Δ3/Δ3 mice occurred without compromising the physiological response to fasting or cold. All metabolic phenotypes were reversed at thermoneutrality, suggesting that basal autonomic activity was required. Direct electrode stimulation of sympathetic neuron exocytosis from Snap25 Δ3/Δ3 inguinal adipose depots resulted in enhanced and prolonged norepinephrine release. Thus, the Gβγ-SNARE interaction represents a cellular mechanism that deserves further exploration as an additional avenue for combating metabolic disease.

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Section: Introductionmentioning

confidence: 99%

Gβγ-SNAP25 exocytotic brake removal enhances insulin action, promotes adipocyte browning, and protects against diet-induced obesity

Ceddia¹,

Zurawski²,

Gray³

et al. 2023

Journal of Clinical Investigation

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Digestion, absorption, and transport properties of soy-fermented douchi hypoglycemic peptides VY and SFLLR under simulated gastrointestinal digestion and Caco-2 cell monolayers

Wang

et al. 2023

Food Research International

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Removing the Gβγ-SNAP25 brake on exocytosis enhances insulin action, promotes adipocyte browning, and protects against diet-induced obesity

Ceddia

Zurawski

et al. 2020

Preprint

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The Gβγ complex inhibits vesicle exocytosis by two mechanisms: inhibiting calcium entry by binding to voltage gated calcium channels, and binding to SNAP25 in the SNAP Receptor (SNARE) complex. To de-convolute the role of each of these mechanisms in vivo, we have made a mouse with the second mechanism disabled. The SNAP25Δ3 mutation renders the SNARE complex deficient in binding to Gβγ and was used to investigate the importance of the Gβγ-SNAP25 interaction in glucose stimulated insulin secretion (GSIS) and global metabolic homeostasis. GSIS and α2A adrenergic receptor-mediated inhibition of GSIS were not altered in SNAP25 Δ3/Δ3 mice. Nevertheless, SNAP25 Δ3/Δ3 mice exhibited a marked improvement in insulin sensitivity and were resistant to weight gain when challenged with a high fat diet (HFD). Reduced food consumption in the early stages of HFD feeding were partly responsible for the inability of SNAP25 Δ3/Δ3 mice to gain weight on HFD. Additionally, improved insulin-mediated glucose uptake into white adipose tissue and increased 'browning' were observed in SNAP25 Δ3/Δ3 mice, which is consistent with an impaired ability to retain energy stores. These phenotypic changes in SNAP25 Δ3/Δ3 mice are all metabolically protective, indicating that pharmacological targeting of the Gβγ-SNAP25 interaction may have a metabolic benefit. Introduction:G-protein coupled receptors (GPCRs) are canonically known to mediate downstream signaling events through the activation of heterotrimeric G-proteins. While the classical Gα-mediated signaling events are well known, and many represent important pharmacological targets (1), signaling via the Gβγ-subunits have received less attention and the therapeutic targeting of these signaling pathways has not been as widely exploited (2).One function of Gβγ is to inhibit exocytosis by two mechanisms, modulation of calcium entry, and direct binding to the exocytotic fusion complex (3). We have shown that Gβγ binding to the SNARE complex is mainly through the last three amino acids of SNAP25 (Soluble N-ethylmaleimide-sensitive factor Attachment Protein), in the SNAP Receptor (SNARE) complex (4). In order to specifically study the contribution of exocytosis at the exocytotic fusion step in vivo, we developed an allele of SNAP25 which lacks these last three amino acids, which we have called SNAP25Δ3 (5). The ability of SNAP25Δ3 to form SNARE complexes that undergo calciumsynaptotagmin mediated zipping and regulate exocytosis is identical to that of SNAP25, but its ability to interact with Gβγ, and GPCR-mediated inhibitory effects on exocytosis, is ablated. The SNAP25 Δ3/Δ3 mouse has demonstrated the importance of the Gβγ-SNARE pathway in a number of neurological processes, including stress and pain processing, as well as long-term potentiation (6) and spatial memory (5). We hypothesized that the SNAP25 Δ3/Δ3 mouse may have an altered metabolic phenotype because neurological processes use SNAREdependent signals to regulate a number of metabolically important processes, such as feeding behavior, ene...

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Exocytosis Proteins: Typical and Atypical Mechanisms of Action in Skeletal Muscle

Cited by 3 publications

References 236 publications

Gβγ-SNAP25 exocytotic brake removal enhances insulin action, promotes adipocyte browning, and protects against diet-induced obesity

Gβγ-SNAP25 exocytotic brake removal enhances insulin action, promotes adipocyte browning, and protects against diet-induced obesity

Digestion, absorption, and transport properties of soy-fermented douchi hypoglycemic peptides VY and SFLLR under simulated gastrointestinal digestion and Caco-2 cell monolayers

Removing the Gβγ-SNAP25 brake on exocytosis enhances insulin action, promotes adipocyte browning, and protects against diet-induced obesity

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