ArfGEF1/2 Inhibition Selectively Blocks Neurogenic ATP Release from Rat Tail Arteries
Notice bibliographique
Résumé
Introduction: Adenosine Triphosphate (ATP) is a versatile neurotransmitter that regulates vasomotor tone in the peripheral nervous systems. The Vesicular Nucleotide Transporter (VNUT) is thought to load ATP into vesicles that mediate purinergic neurotransmission and is unique amongst its relatives. Bioinformatics and AI-modelling in our lab shows that mammalian VNUT contains an endoplasmic reticulum (ER)-Golgi retention sequence and lacks synaptic vesicle and lysosome targeting motifs present in VNUT’s relatives. Our work in cultured cells suggests that VNUT localizes to sorting compartments akin to endosomes, ER and Golgi, as opposed to traditional acidic synaptic vesicles, like those that contain catecholamines. Critically, little is known of the molecular basis of differential release and recycling of purinergic and adrenergic vesicles in sympathetic neurons. We hypothesized that inhibiting ADP-ribosylation factor guanine nucleotide exchange factors (ArfGEFs) GBF1, ArfGEF1, and ArfGEF2 would preferentially attenuate purinergic signalling in contrast to adrenergic (norepinephrine) signalling in the rat tail artery, consistent with VNUT localization to an endosomal/Golgi/ER-resembling compartment. Methods: Male and female rat tail arteries were studied by field-stimulated wire myography and epifluorescence immunofluorescence microscopy. Results: Inhibiting ArfGEFs 1 and 2 selectively attenuated electrically-stimulated ATP release from the perivascular nerves of rat tail arteries while leaving adrenergic release unaffected. This effect was not use-dependent. Brefeldin-A, an inhibitor of ArfGEFs 1, 2, and GBF1, attenuated ATP-dependent arterial tension. Golgicide-A – inhibitor of GBF1 – did not significantly attenuate tension, indicating a likely role for ArfGEF1 and or ArfGEF2 in the maintenance of releasable ATP stores in rat tail artery. Immunostaining confirmed that VNUT localizes to perivascular nerves and does not colocalize with traditional vesicle markers (e.g. Syt1, SV2A). In addition, we observed markers of ER (calreticulin) and Golgi satellites in perivascular nerves, with partial colocalization of VNUT with trans-golgi markers. We also observed sex-differences in ATP-dependent vasomotor responses, where male rat arteries demonstrated greater ATP-driven vasomotor responses compared to female tissues. Conclusions: These findings demonstrate the first report of differential dependence of ATP and NE release on vesicle trafficking regulators and adaptor proteins. In addition, we show functional evidence supporting VNUT localization to an uncharacterized compartment that requires ArfGEFs 1 and/or 2 pathways to load ATP into vesicles. Observed sex differences in neurogenic vasomotor tone are consistent with recent reports studying mesenteric arteries. This work was supported by grant RGPIN-2019-04925 from the Natural Sciences and Engineering Research Council (NSERC) of Canada. This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.
Récupéré en direct depuis OpenAlex et désinversé. Les résumés ne sont pas conservés dans cette base de données : les index inversés représentent 8,6 Go des 9,3 Go de texte de la base, et le serveur dispose de 13 Go libres.
Comment cette classification a été obtenuedéplier
Prédiction distillée sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Apprise à partir de 10 348 étiquettes directes de Codex et de 10 348 étiquettes directes de Gemma. Le mode candidate est l'union des têtes enseignantes seuillées; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont ni des étiquettes humaines ni des étiquettes directes de modèles de pointe.
Scores Codex et Gemma par catégorie
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,000 | 0,000 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,000 | 0,000 |
| Bibliométrie | 0,000 | 0,000 |
| Études des sciences et des technologies | 0,000 | 0,000 |
| Communication savante | 0,000 | 0,000 |
| Science ouverte | 0,000 | 0,000 |
| Intégrité de la recherche | 0,000 | 0,000 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,000 | 0,000 |
Scores machine (provisoires)
Les deux têtes enseignantes du modèle étudiant, lues sur ce travail. Un score ordonne la base pour la relecture; il n'affirme jamais une catégorie, et le statut de validation accompagne chaque rangée tel quel.
Scores de référence d'un modèle non mature (critères de maturité non atteints, 7 itérations). Un score ordonne; il n'affirme jamais une catégorie.
score_only:v0-immature-baseline · tel quel depuis la passe de notation : score_only signifie que le nombre peut ordonner les travaux, et qu'aucune étiquette de catégorie n'en découleClassification
machine, non validéePrédiction automatique; un appel candidat d’une seule tête enseignante, pas un consensus.
Le détail, modèle par modèle et score par score, se trouve en fin de page sous « Comment cette classification a été obtenue ».