Soluble guanylyl cyclase is a critical regulator of migraine-associated pain

Aissa, Manel Ben; Tipton, Alycia F; Bertels, Zachariah; Gandhi, Ronak G.; Moye, Laura S.; Novack, Madeline; Bennett, Brian M.; Wang, Yueting; Litosh, Vladislav A.; Lee, Sue; Gaisina, Irina N.; Thatcher, Gregory R. J.; Pradhan, Amynah

doi:10.1177/0333102417737778

Cited by 46 publications

(45 citation statements)

References 69 publications

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“…Further, in a recent study, direct activation of sGC by the novel sGC stimulator, VL-102, also produced cephalic pain, which was sensitive to both acute and preventive migraine treatments. In addition, VL-102 treatment also increased expression of the pro-migraine neuropeptide CGRP in trigeminal ganglia [38]. In parallel, the sGC inhibitor, ODQ, completely blocked migraine-associated acute and chronic pain evoked by NTG, again supporting the action of NTG through the sGC-cGMP pathway.…”

Section: Soluble Guanylyl Cyclase (Sgc) Inhibitors and Migrainementioning

confidence: 67%

“…Interestingly, ODQ also effectively inhibited established chronic migraine-associated pain, in the absence of exogenous NO stimulation. These intriguing data indicate that a chronic migraine state could be maintained by an upregulation in endogenous NOS activity [38]. Thus, blocking this maladaptation could help to reset the chronic migraine brain.…”

Section: Soluble Guanylyl Cyclase (Sgc) Inhibitors and Migrainementioning

confidence: 89%

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Targeted Nitric Oxide Synthase Inhibitors for Migraine

2018

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Nitric oxide (NO) is a small gaseous signaling molecule that has important biological effects. It has been heavily implicated in migraine; and the NO donor, nitroglycerin, has been used extensively as a human migraine trigger. Correspondingly, a number of components of the NO signaling cascade have been shown to be upregulated in migraine patients. NO is endogenously produced in the body by NO synthase (NOS), of which there are three isoforms: neuronal NOS (nNOS), endothelial NOS (eNOS), and inducible NOS (iNOS). Based on the accumulating evidence that endogenous NO regulation is altered in migraine pathogenesis, global and isoform-selective inhibitors of NOS have been targeted for migraine drug development. This review highlights the evidence for the role of NO in migraine and focuses on the use of NOS inhibitors for the treatment of this disorder. In addition, we discuss other molecules within the NO signaling pathway that may be promising therapeutic targets for migraine.

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Section: Soluble Guanylyl Cyclase (Sgc) Inhibitors and Migrainementioning

confidence: 67%

Section: Soluble Guanylyl Cyclase (Sgc) Inhibitors and Migrainementioning

confidence: 89%

Targeted Nitric Oxide Synthase Inhibitors for Migraine

2018

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“…126 In addition, a sGC inhibitor, ODQ, completely abolished migraine-associated allodynia induced by nitroglycerin. 126 Interestingly, in a chronic migraine model, ODQ was also able to inhibit established allodynia in the absence of an exogenous NO donor, which suggests that upregulation of the sGC pathway may be a key mediator for the maintenance of the chronic migraine state. This study strengthens the connection between the NO-sGC pathway and headache, and open the possibility for inhibitors or negative modulators of sGC as novel migraine therapeutics.…”

Section: Nitric Oxide Pathwaymentioning

confidence: 96%

“…In a preclinical study, direct activation of the sGC pathway by the novel sGC stimulator, VL‐102, produced cephalic allodynia which was blocked by known migraine treatments . In addition, a sGC inhibitor, ODQ, completely abolished migraine‐associated allodynia induced by nitroglycerin . Interestingly, in a chronic migraine model, ODQ was also able to inhibit established allodynia in the absence of an exogenous NO donor, which suggests that upregulation of the sGC pathway may be a key mediator for the maintenance of the chronic migraine state.…”

Section: Nitric Oxide Pathwaymentioning

confidence: 97%

Emerging Treatment Targets for Migraine and Other Headaches

Bertels

Pradhan

2019

Headache

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Migraine is a complex disorder that is characterized by an assortment of neurological and systemic effects. While headache is the most prominent feature of migraine, a host of symptoms affecting many physiological functions are also observed before, during, and after an attack. Furthermore, migraineurs are heterogeneous and have a wide range of responses to migraine therapies. The recent approval of calcitonin gene‐related‐peptide based therapies has opened up the treatment of migraine and generated a renewed interest in migraine research and discovery. Ongoing advances in migraine research have identified a number of other promising therapeutic targets for this disorder. In this review, we highlight emergent treatments within the following biological systems: pituitary adenylate cyclase activating peptdie, 2 non‐mu opioid receptors that have low abuse liability – the delta and kappa opioid receptors, orexin, and nitric oxide‐based therapies. Multiple mechanisms have been identified in the induction and maintenance of migraine symptoms; and this divergent set of targets have highly distinct biological effects. Increasing the mechanistic diversity of the migraine tool box will lead to more treatment options and better patient care.

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“…Inhibition of GC-1 may seem counterintuitive, but several groups have targeted GC-1 in cases of migraines [85], septic shock [86], cancer [87,88], and neurological disorders such as Parkinson’s Disease [89]. Structural characterization of the inhibited C1/C2 adenylyl cyclase domain has alluded to key structural elements involved in domain activation, which could be applied to αβGC cat .…”

Section: Structural Determinants For Catalytic Activitymentioning

confidence: 99%

Structure/function of the soluble guanylyl cyclase catalytic domain

Childers

Garcin

2018

Nitric Oxide

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Soluble guanylyl cyclase (GC-1) is the primary receptor of nitric oxide (NO) in smooth muscle cells and maintains vascular function by inducing vasorelaxation in nearby blood vessels. GC-1 converts guanosine 5′-triphosphate (GTP) into cyclic guanosine 3′,5′-monophosphate (cGMP), which acts as a second messenger to improve blood flow. While much work has been done to characterize this pathway, we lack a mechanistic understanding of how NO binding to the heme domain leads to a large increase in activity at the C-terminal catalytic domain. Recent structural evidence and activity measurements from multiple groups have revealed a low-activity cyclase domain that requires additional GC-1 domains to promote a catalytically-competent conformation. How the catalytic domain structurally transitions into the active conformation requires further characterization. This review focuses on structure/function studies of the GC-1 catalytic domain and recent advances various groups have made in understanding how catalytic activity is regulated including small molecules interactions, Cys-S-NO modifications and potential interactions with the NO-sensor domain and other proteins.

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Soluble guanylyl cyclase is a critical regulator of migraine-associated pain

Cited by 46 publications

References 69 publications

Targeted Nitric Oxide Synthase Inhibitors for Migraine

Targeted Nitric Oxide Synthase Inhibitors for Migraine

Emerging Treatment Targets for Migraine and Other Headaches

Structure/function of the soluble guanylyl cyclase catalytic domain

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