Hypofunctionality of Gi Proteins as Aetiopathogenic Mechanism for Migraine and Cluster Headache

Abstract

The involvement of Gi proteins in the modulation of pain perception has been widely established, and mutations in G-proteins have already been identified as the aetiopathological cause of human diseases. The aim of the present study was to determine whether a deficiency or a hypofunctionality of the Gi proteins occurred in primary headache. The functionality and the level of expression of Gi proteins were investigated in lymphocytes from migraine without aura, migraine with aura and cluster headache sufferers. A reduced capability to inhibit forskolin-stimulated adenylyl cyclase activity in headache patients was observed. Migraine patients also showed basal adenosine cAMP levels about four times higher than controls. The reduced activity of Gi proteins seems not to be related to a reduction of protein levels since no significant reduction of the Gialpha subunits was observed. These results indicate Gi protein hypofunctionality as an aetiopathogenic mechanism in migraine and cluster headache.

Neurophysiology of Migraine

“…Moreover, a recent biochemical study showed a reduced activity of Gi proteins in headache subjects suffering from migraine or cluster headache, together with 4-fold elevated levels of adenosine cAMP compared to controls [18]. Since Gi protein activation reduces cell excitability and cAMP has a vasodilator effect, the authors suggest that these data may represent the biological basis for the neuronal hyperexcitability observed in migraine, which in turn accounts for the observed hypersensitivity to environmental stimuli.…”

Triptans in clinical practice: the basic scientist’s point of view

“…Involvement of Gi proteins in the modulation of pain perception has been established and lack of its function enhances the sensitivity to pain. A hypofunctionality of Gi proteins has been recently documented in migraine patients [21]. Restoration of normal function of this system may be a possible explanatory key for the efficacy of short-term prophylaxis with triptans, for example in menstrual migraine.…”

Genetics of Cluster Headache

“…Hence, triptan-stimulated 5-HT 1B/D receptors might generate increased intracellular signals in 825T allele carriers, ultimately leading to an improved drug response. Interestingly, a reduced activity of G proteins from the G i family was found in CH and migraine patients [47]. Assuming that this also affects 5-HT 1B/D signalling, presence of the GNB3 825T allele might compensate for this.…”