Haplotype Analysis Confirms the Association Between the <i>HCRTR2</i> Gene and Cluster Headache

Rainero, Innocenzo; Gallone, Salvatore; Rubino, Elisa; Ponzo, Paola; Valfrè, Walter; Binello, E; Fenoglio, Pierpaola; Gentile, Salvatore; Anoaica, Mihaela; Gasparini, Mauro; Pinessi, Lorenzo

doi:10.1111/j.1526-4610.2008.01080.x

Cited by 48 publications

(64 citation statements)

References 31 publications

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“…This complex behavior of selective OX antagonist in the VTA neurons might well indicate the formation of heterodimers/oligomers by both receptors. Indeed, the residue hOX 2 -Val308 (corresponds to hOX 1 -Val302, located on the transmembrane 6 on the outer surface of the receptor) seems to be involved in OX 2 dimerization, and the 1246GϾA polymorphism (substitution of valine 308 by isoleucine) of the OX 2 gene has been suggested to modulate the genetic risk for cluster headaches by interfering with this dimerization process (Rainero et al, 2008). Furthermore, a report investigating the coexpression of OX 1 and cannabinoid CB1 has shown that the heterodimerization of OX 1 -CB1 receptors resulted in both ligand-dependent and -independent coordinated alterations of receptor localization and function (Ellis et al, 2006).…”

Section: Discussionmentioning

confidence: 99%

Biochemical and Electrophysiological Characterization of Almorexant, a Dual Orexin 1 Receptor (OX₁)/Orexin 2 Receptor (OX₂) Antagonist: Comparison with Selective OX₁ and OX₂ Antagonists

et al. 2009

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Recent preclinical and clinical research has shown that almorexant promotes sleep in animals and humans without disrupting the sleep architecture. Here, the pharmacology and kinetics of [ 3 H]almorexant binding to human orexin 1 receptor (OX 1 )-and human orexin 2 receptor (OX 2 )-human embryonic kidney 293 membranes were characterized and compared with those of selective OX 1 and OX 2 antagonists, including 1- -408124), and N-ethyl-2-[(6-methoxy-pyridin-3-yl)-(toluene-2-sulfonyl)-amino]-N-pyridin-3-ylmethyl-acetamide (EMPA). The effect of these antagonists was also examined in vitro on the spontaneous activity of rat ventral tegmental area (VTA) dopaminergic neurons. [3 H]Almorexant bound to a single saturable site on hOX 1 and hOX 2 with high affinity (K d of 1.3 and 0.17 nM, respectively). In Schild analyses using the [ 3 H]inositol phosphates assay, almorexant acted as a competitive antagonist at hOX 1 and as a noncompetitive-like antagonist at hOX 2 . In binding kinetic analyses, [ 3 H]almorexant had fast association and dissociation rates at hOX 1 , whereas it had a fast association rate and a remarkably slow dissociation rate at hOX 2 . In the VTA, orexin-A potentiated the basal firing frequency to 175 Ϯ 17% of control in approximately half of the neurons tested. In the presence of 1 M SB-674042 or SB-408124, the effect of orexin-A was only partially antagonized. However, in the presence of 1 M EMPA or 1 M almorexant, the effect of orexin-A was completely antagonized. In conclusion, almorexant exhibited a noncompetitive and long-lasting pseudo-irreversible mode of antagonism as a result of its very slow rate of dissociation from OX 2 . The electrophysiology data suggest that OX 2 might be more important than OX 1 in mediating the effect of orexin-A on slow-firing of VTA dopaminergic neurons.Orexins (also called hypocretins) belong to a family of neuropeptides that are exclusively synthesized in the neuronal cell bodies of the lateral hypothalamic areas. Orexin-A/hypocretin-1 (33 amino acids) and orexin-B/hypocretin-2 (28 amino acids) are derived from the proteolytic processing of 130 amino acid polypeptide prepro-orexin (de Lecea et al., Article, publication date, and citation information can be found at

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Section: Discussionmentioning

confidence: 99%

Biochemical and Electrophysiological Characterization of Almorexant, a Dual Orexin 1 Receptor (OX₁)/Orexin 2 Receptor (OX₂) Antagonist: Comparison with Selective OX₁ and OX₂ Antagonists

et al. 2009

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“…The 1246 G>A polymorphism of the OX 2 R gene (HCRT2) has been reported to associate signifi cantly with an increased risk of CH. Patients homozygous for the G allele, in comparison to the remaining genotypes, are fi vefold more likely to develop the disorder [36]. However, this link was not found in a Danish study [37] and was shown to have no association with treatment response [38].…”

Section: Orexins and Cluster Headachementioning

confidence: 95%

Cluster headache, hypothalamus, and orexin

Holland

Goadsby²

2009

Current Science Inc

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Cluster headache (CH) is a highly disabling condition resulting in severe, recurrent unilateral bouts of pain and accompanying autonomic symptoms. This review describes some current views regarding the underlying pathophysiology covering the pain and cranial autonomic (parasympathetic) activation, and highlights the potential importance of the hypothalamus in CH. The hypothalamus is known to modulate many functions and has been shown to be involved in the pathophysiology of a variety of primary headaches, including CH. Hypothalamic structures are likely to underlie the circadian and circannual periodicity of attacks and contribute to the pain and autonomic disturbances. We discuss the hypothalamic involvement in CH and modulation of trigeminovascular processing and examine the emerging involvement of the hypothalamic orexinergic system as a possible key pathway in CH pathophysiology.

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“…However, the functional relevance of the G>A nucleotide exchange, which leads to a substitution of valine at position 308 by isoleucine, remains unclear. The Italian group that first reported the association made an initial step in the direction of deciphering the biological mechanisms involved [33]. They first genotyped five new polymorphisms in the HCRTR2 gene, for two of which the allele and genotype distribution was significantly different between CH patients and controls (rs3122156, rs2653342).…”

Section: Candidate Gene Approachesmentioning

confidence: 99%

“…Finally, computer simulation did not indicate an effect of the amino acid change at the hypocretin-binding site. It was suggested that the dimerization process of the receptor may be affected [33].…”

Section: Candidate Gene Approachesmentioning

confidence: 99%

Genetics of Cluster Headache

Schürks

2010

Curr Pain Headache Rep

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Cluster headache (CH) is a rare, excruciating primary headache disorder. A genetic basis has been suggested by family and twin studies, but the mode of transmission seems to vary and the amount of heritability is unclear. The number of genetic association studies investigating variants implicated in the pathophysiology of CH is limited. The HCRTR2 1246G > A and the ADH4 925A > G polymorphisms have been associated with CH. The former has been confirmed and may affect the hypothalamic hypocretin system. However, it only appears to account for a part of the genetic susceptibility for CH, and additional genetic and environmental factors are likely implicated. Pharmacogenetic studies have suggested that the GNB3 825C > T polymorphism may modify treatment response to triptans among CH patients by altering the signal transduction cascade via G protein-coupled receptors. Genetic studies in CH are notoriously difficult due to the complex nature of the disorder and the low prevalence of CH.

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Haplotype Analysis Confirms the Association Between the HCRTR2 Gene and Cluster Headache

Cited by 48 publications

References 31 publications

Biochemical and Electrophysiological Characterization of Almorexant, a Dual Orexin 1 Receptor (OX₁)/Orexin 2 Receptor (OX₂) Antagonist: Comparison with Selective OX₁ and OX₂ Antagonists

Biochemical and Electrophysiological Characterization of Almorexant, a Dual Orexin 1 Receptor (OX₁)/Orexin 2 Receptor (OX₂) Antagonist: Comparison with Selective OX₁ and OX₂ Antagonists

Cluster headache, hypothalamus, and orexin

Genetics of Cluster Headache

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Haplotype Analysis Confirms the Association Between the HCRTR2 Gene and Cluster Headache

Cited by 48 publications

References 31 publications

Biochemical and Electrophysiological Characterization of Almorexant, a Dual Orexin 1 Receptor (OX1)/Orexin 2 Receptor (OX2) Antagonist: Comparison with Selective OX1 and OX2 Antagonists

Biochemical and Electrophysiological Characterization of Almorexant, a Dual Orexin 1 Receptor (OX1)/Orexin 2 Receptor (OX2) Antagonist: Comparison with Selective OX1 and OX2 Antagonists

Cluster headache, hypothalamus, and orexin

Genetics of Cluster Headache

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Biochemical and Electrophysiological Characterization of Almorexant, a Dual Orexin 1 Receptor (OX₁)/Orexin 2 Receptor (OX₂) Antagonist: Comparison with Selective OX₁ and OX₂ Antagonists

Biochemical and Electrophysiological Characterization of Almorexant, a Dual Orexin 1 Receptor (OX₁)/Orexin 2 Receptor (OX₂) Antagonist: Comparison with Selective OX₁ and OX₂ Antagonists