Neuronal calcium channels in migraine

Research project P 14541 Neuronal calcium channels in migraine Jörg STRIESSNIG 09.10.2000 Migraine is a frequent neurological disorder affecting 5-15% of the population in developed countries causing a substantial socioeconomic burden. Although functional changes of neuronal activity and cerebral hemodynamics have been described, the pathophysiological mechanisms underlying recurrent migraine attacks are not well understood. Recent neurogenetic and electrophysiological studies indicate that missense mutations within the alpha1A subunit of a neuronal voltage-gated P/Q-type calcium channel cause a rare form of hereditary migraine, familial hemiplegic migraine (FHM). This channel dysfunction is believed to cause neuronal instability that eventually triggers the pathophysiological changes associated with migraine attacks. FHM therefore provides a unique disease model which should allow to relate the functional disturbances of an ion channel to alterations in the electric properties of single neurons and neuronal signaling. In the proposed project we will analyze the genotype - phenotype, relationship of FHM mutations to better understand how disturbed neuronal calcium channel activity can participate in the pathophysiology of migraine. We will test the hypothesis that alterations in calcium channel gating represent the predominant functional abnormality induced by FHM mutations. We will also investigate why other structural aberrations of the alphalA subunit cause a different clinical phenotype, episodic ataxia type-2 (EA-2). We will test the attractive hypothesis that EA-2 mutations completely abolish alpha1A - mediated calcium channel activity and that the inactive subunits could perhaps serve as alpha I A-subunit scavengers. Our experiments should not only provide important insight into the pathophysiology of these episodic diseases but also into more common forms of migraine. Important predictions about the usefulness of P/Q-type calcium channel modulators for migraine therapy should be possible.

Familial Hemiplegic migraine type-1 (FHM1) is a human disease resulting from mutations in a certain isoform of neuronal voltage-gated calcium channels (P/Q-type calcium channels). Similar to targeted mutations in mice, this disease represents a unique model to study the pathophysiology of migraine which is largely unknown. An important open question is how migraine attacks are initiated. Studies in patients with common forms of migraine indicate the existence of hyperexcitability in the cerebral cortex. We analyzed the consequences of individual FHM1 mutations on channel gating and expression to predict how this can cause neuronal dysfunction that finally leads to FHM1. We discovered that 9 out of 10 of the 16 known FHM1 mutations all change the opening and closing behavior (gating) of these channels. One intriguing change found for all mutations was the facilitation of channel opening at membrane potentials that would only be reached during very weak stimulation of neurons. Therefore during weak stimuli a release of the excitatory transmitter glutamate would occur in neurons of FHM1 patients but not in individuals without these mutations. One major finding was that the channel`s ß-subunits also qualitatively and quantitatively determine how FHM1 mutations affect channel gating. ß-subunits form part of the channel complex and it is believed that each channel complex associates with a single ß-subunit. However, at least four different ß-subunit isoforms (ß1-ß4) are known which all four associate with P/Q-type channels. Interestingly, for one FHM1 mutation we found the typical facilitation of channel opening only with the ß1 subunit but not with ß3 and ß4 subunits. Likewise, other mutational changes were expressed in a ß-subunit isoform specific manner. Taken together we could show that facilitation of neurotransmitter release is a common pathogenetic mechanism in FHM1. This can nicely explain the hyperexcitability of cortical neurons that is also found in more common forms of migraine. Further research now aims to investigate if the FHM1 mutations can also alter the targeting of P/Q- type calcium channels to different regions of a neuron and if ß-subunit - specific mutational effects are a general phenomenon applying to the majority of FHM1 mutations. As some FHM1 mutations also lead to permanent cerebellar dysfunction, we will investigate if this clinical phenotype correlates with defined FHM1-induced changes in channel function when associated with ß4 subunits, because this ß-isoform is the most prominent in cerebellar neurons.