Rare GPR37L1 variants reveal potential roles in anxiety and migraine disorders DOI Open Access
Gerda E. Breitwieser, Andrea Cippitelli, Yingcai Wang

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2023, Volume and Issue: unknown

Published: July 7, 2023

Abstract GPR37L1 is an orphan receptor that couples through heterotrimeric G-proteins to regulate physiological functions. Since its role in humans not fully defined, we used unbiased computational approach assess the clinical significance of rare genetic variants found among 51,289 whole exome sequences from DiscovEHR cohort. Briefly, coding were binned according predicted pathogenicity, and analyzed by Sequence Kernel Association testing reveal significant associations with disease diagnostic codes for epilepsy migraine, others. do prove causality, then functionally SK-N-MC cells evaluate potential signaling differences pathogenicity. Notably, exhibited varying abilities reduce cAMP levels, activate MAPK signaling, and/or upregulate expression response agonist prosaptide (TX14(A)), as compared wild-type receptor. In addition changes, knockout or certain altered cellular cholesterol which also acutely regulated administration TX14(A) via activation pathway. Finally, simulate impact nonsense large patient cohort, a (KO) mouse line lacking Gpr37L1 was generated, revealing loss this produced sex-specific changes implicated migraine-related disorders. Collectively, these observations define existence human population are associated neuropsychiatric conditions identify underlying vivo actions pathological processes leading anxiety migraine. SIGNIFICANCE STATEMENT G-protein coupled receptors (GPCRs) represent diverse group membrane contribute wide range diseases serve effective drug targets. However, number have no identified ligands functions, i.e., receptors. Over past decade, advances been made, but there need identifying new strategies their roles health disease. Our results highlight utility variant analyses associations, functional relevant animal systems, ultimately novel targets treatment neurological disorders lack wide-spread efficacy.

Language: Английский

Mechanisms underlying CSD initiation implicated by genetic mouse models of migraine DOI Creative Commons
Daniela Pietrobon, K. C. Brennan

The Journal of Headache and Pain, Journal Year: 2025, Volume and Issue: 26(1)

Published: Jan. 27, 2025

Language: Английский

Citations

0
Rare GPR37L1 Variants Reveal Potential Association between GPR37L1 and Disorders of Anxiety and Migraine DOI
Gerda E. Breitwieser, Andrea Cippitelli, Yingcai Wang

et al.

Journal of Neuroscience, Journal Year: 2024, Volume and Issue: 44(19), P. e1226232024 - e1226232024

Published: April 3, 2024

GPR37L1 is an orphan receptor that couples through heterotrimeric G-proteins to regulate physiological functions. Since its role in humans not fully defined, we used unbiased computational approach assess the clinical significance of rare

Language: Английский

Citations

2
Targeting Na,K-ATPase-Src signaling to normalize cerebral blood flow in a murine model of familial hemiplegic migraine DOI
Christian Staehr, Halvor Guldbrandsen, Casper Homilius

et al.

Journal of Cerebral Blood Flow & Metabolism, Journal Year: 2024, Volume and Issue: unknown

Published: Dec. 4, 2024

Familial hemiplegic migraine type 2 (FHM2) is linked to Na,K-ATPase α 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 targeting Na,K-ATPase-dependent phosphorylation pNaKtide would normalize cerebral perfusion coupling in [Formula: text] mice. The effect on blood flow was assessed using laser speckle contrast imaging awake, head-fixed mice cranial windows a longitudinal design. At baseline, compared wild type, exhibited increased middle artery tone; whisker stimulation leading an increase sensory cortex flow. No difference between genotypes telemetrically pressure occurred. K ir 2.1 channel expression endothelium. Two weeks treatment normalized tone, endothelial expression, Inhibition the signaling prevented excessive vasoconstriction disturbances had only minor hypotensive similar both genotypes. These results demonstrate novel target FHM2.

Language: Английский

Citations

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

Xue-Ying Ke,

Chen Jiang

et al.

Phytomedicine, Journal Year: 2024, Volume and Issue: 136, P. 156349 - 156349

Published: Dec. 27, 2024

Language: Английский

Citations

1
Traditional Chinese Medicine Use in the Pathophysiological Processes of Migraine DOI Creative Commons
Meirong Wu,

Yi Ou,

Rui Han

et al.

World Journal of Traditional Chinese Medicine, Journal Year: 2024, Volume and Issue: unknown

Published: Sept. 21, 2024

Abstract Migraine is a highly prevalent neurological disorder and has been the second leading cause of disability worldwide for many years. The pathophysiology migraines complicated, most available medications have unpleasant side effects. Therefore, it essential to understand mechanism migraine develop potential preventive therapeutic agents. Studies confirmed that traditional Chinese medicine (TCM) can alleviate by reducing neuroinflammation, oxidative stress, apoptosis regulating neurotransmitters vascular function. Starting from pathophysiological process migraine, this review summarizes mechanisms which TCM improves neurovascular function after provide clues reference clinical application in prevention treatment guide further research development new drugs.

Language: Английский

Citations

0
1H-MRS reveals abnormal energy metabolism and excitatory-inhibitory imbalance in a chronic migraine-like state induced by nitroglycerin in mice DOI Creative Commons

Jinggui Gao,

Da Wang, Chenlu Zhu

et al.

The Journal of Headache and Pain, Journal Year: 2024, Volume and Issue: 25(1)

Published: Sept. 30, 2024

Language: Английский

Citations

0
Rare GPR37L1 variants reveal potential roles in anxiety and migraine disorders DOI Open Access
Gerda E. Breitwieser, Andrea Cippitelli, Yingcai Wang

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2023, Volume and Issue: unknown

Published: July 7, 2023

Abstract GPR37L1 is an orphan receptor that couples through heterotrimeric G-proteins to regulate physiological functions. Since its role in humans not fully defined, we used unbiased computational approach assess the clinical significance of rare genetic variants found among 51,289 whole exome sequences from DiscovEHR cohort. Briefly, coding were binned according predicted pathogenicity, and analyzed by Sequence Kernel Association testing reveal significant associations with disease diagnostic codes for epilepsy migraine, others. do prove causality, then functionally SK-N-MC cells evaluate potential signaling differences pathogenicity. Notably, exhibited varying abilities reduce cAMP levels, activate MAPK signaling, and/or upregulate expression response agonist prosaptide (TX14(A)), as compared wild-type receptor. In addition changes, knockout or certain altered cellular cholesterol which also acutely regulated administration TX14(A) via activation pathway. Finally, simulate impact nonsense large patient cohort, a (KO) mouse line lacking Gpr37L1 was generated, revealing loss this produced sex-specific changes implicated migraine-related disorders. Collectively, these observations define existence human population are associated neuropsychiatric conditions identify underlying vivo actions pathological processes leading anxiety migraine. SIGNIFICANCE STATEMENT G-protein coupled receptors (GPCRs) represent diverse group membrane contribute wide range diseases serve effective drug targets. However, number have no identified ligands functions, i.e., receptors. Over past decade, advances been made, but there need identifying new strategies their roles health disease. Our results highlight utility variant analyses associations, functional relevant animal systems, ultimately novel targets treatment neurological disorders lack wide-spread efficacy.

Language: Английский

Citations

0