Astrocytic Glutamate Transporters and Migraine

Conti, Fiorenzo; Pietrobon, Daniela

doi:10.1007/s11064-022-03849-w

Cited by 6 publications

(1 citation statement)

References 159 publications

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“…One specific mechanism involves dysregulation of glutamate homeostasis [4,5]. While some rare monogenic disorders point to a direct role in neurons, other studies indicate a protective role in astrocytes to counteract the effects of such dysregulation [55,56]. Based on human clinical data, astrocyte localization, and functional studies, we posit a role for GPR37L1 signaling in the latter scenario.…”

Section: Assessing In Vivo Role(s) For Gpr37l1mentioning

confidence: 88%

Rare GPR37L1 variants reveal potential roles in anxiety and migraine disorders

Breitwieser,

Cippitelli,

Wang

et al. 2023

Preprint

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GPR37L1 is an orphan receptor that couples through heterotrimeric G-proteins to regulate physiological functions. Since its role in humans is not fully defined, we used an unbiased computational approach to assess the clinical significance of rare GPR37L1 genetic variants found among 51,289 whole-exome sequences from the DiscovEHR cohort. Briefly, rare GPR37L1 coding variants were binned according to predicted pathogenicity, and then analyzed by Sequence Kernel Association testing to reveal significant associations with disease diagnostic codes for generalized epilepsy and migraine, among others. Since associations do not prove causality, rare GPR37L1 variants were then functionally analyzed in SK-N-MC cells to evaluate potential signaling differences and pathogenicity. Notably, receptor variants exhibited varying abilities to reduce cAMP levels, activate MAPK signaling, and/or upregulate receptor expression in response to the agonist prosaptide (TX14(A)), as compared to wild-type receptor. In addition to signaling changes, knockout of GPR37L1 or expression of certain rare variants altered cellular cholesterol levels, which were also acutely regulated by administration of the agonist TX14(A) via activation of the MAPK pathway. Finally, to simulate the impact of rare nonsense variants found in the large patient cohort, a knockout (KO) mouse line lacking Gpr37L1 was generated, revealing loss of this receptor produced sex-specific changes implicated in migraine-related disorders. Collectively, these observations define the existence of rare GPR37L1 variants in the human population that are associated with neuropsychiatric conditions and identify the underlying signaling changes that are implicated in the in vivo actions of this receptor in pathological processes leading to anxiety and migraine.

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Section: Assessing In Vivo Role(s) For Gpr37l1mentioning

confidence: 88%

Rare GPR37L1 variants reveal potential roles in anxiety and migraine disorders

Breitwieser,

Cippitelli,

Wang

et al. 2023

Preprint

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Na+-K+-ATPase/GLT-1 interaction participates in EGCG protection against cerebral ischemia-reperfusion injury in rats

Liu,

Ke,

Jiang

et al. 2024

Phytomedicine

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Targeting Na,K-ATPase-Src signaling to normalize cerebral blood flow in a murine model of familial hemiplegic migraine

Staehr,

Guldbrandsen,

Homilius

et al. 2024

J Cereb Blood Flow Metab

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Familial hemiplegic migraine type 2 (FHM2) is linked to Na,K-ATPase α2 isoform mutations, including that of G301R. Mice heterozygous for this mutation ([Formula: see text]) show cerebrovascular hypercontractility associated with amplified Src kinase signaling, and exaggerated neurovascular coupling. This study hypothesized that targeting Na,K-ATPase-dependent Src phosphorylation with pNaKtide would normalize cerebral perfusion and neurovascular coupling in [Formula: see text] mice. The effect of pNaKtide on cerebral blood flow and neurovascular coupling was assessed using laser speckle contrast imaging in awake, head-fixed mice with cranial windows in a longitudinal study design. At baseline, compared to wild type, [Formula: see text] mice exhibited increased middle cerebral artery tone; with whisker stimulation leading to an exaggerated increase in sensory cortex blood flow. No difference between genotypes in telemetrically assessed blood pressure occurred. The exaggerated neurovascular coupling in [Formula: see text] mice was associated with increased Kir2.1 channel expression in cerebrovascular endothelium. Two weeks pNaKtide treatment normalized cerebral artery tone, endothelial Kir2.1 expression, and neurovascular coupling in [Formula: see text] mice. Inhibition of the Na,K-ATPase-dependent Src kinase signaling with pNaKtide prevented excessive vasoconstriction and disturbances in neurovascular coupling in [Formula: see text] mice. pNaKtide had only minor hypotensive effect similar in both genotypes. These results demonstrate a novel treatment target to normalize cerebral perfusion in FHM2.

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Astrocytic Glutamate Transporters and Migraine

Cited by 6 publications

References 159 publications

Rare GPR37L1 variants reveal potential roles in anxiety and migraine disorders

Rare GPR37L1 variants reveal potential roles in anxiety and migraine disorders

Na+-K+-ATPase/GLT-1 interaction participates in EGCG protection against cerebral ischemia-reperfusion injury in rats

Targeting Na,K-ATPase-Src signaling to normalize cerebral blood flow in a murine model of familial hemiplegic migraine

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