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Expression of BKCa channels in the trigeminovascular system - relevance for migraine pathophysiology

Helle Wulf Johansson


The Ph.D. thesis is based upon four studies describing the expression of BKCa channels in tissues related to migraine. The vascular tissues include rat/porcine basilar artery (BA), rat/porcine middle cerebral artery (MCA) and rat middle meningeal artery (MMA). The neuronal tissues include rat/porcine TG (TG) and rat trigeminal nucleus caudalis (TNC). Molecular biology methods were used to identify the expression of BKCa channels in vascular and neuronal tissues. The techniques included RT-PCR to detect mRNA, in situ hybridization to locate the mRNA, western blotting to detect translated protein, histochemistry to locate the protein, double immunofluorescence labelling to investigate for co-localization and ex vivo experiments to study the functionality of BKCa proteins in TG and TNC using the BKCa channel opener NS11021 and the BKCa channel blocker iberiotoxin.

Results from the vascular studies.
BKCa channel mRNA expression was detected in all arteries studied. Higher expression patterns of BKCa mRNA were observed in BA as compared to MCA and MMA. At the protein level BKCa channels were more expressed in BA as compared to MCA and MMA. The BKCa mRNA was localized to the smooth muscle cells and immunofluorescent imaging also verified the BKCa channel protein to the smooth muscle cells using the _-actin marker. The modulatory _1-subunit was detected in BA and MCA.

Results from the neuronal studies.
BKCa channel mRNA expression was detected in TG and TNC. No differences were found at the mRNA level comparing TG and TNC. The BKCa channel protein was shown in TG and TNC with higher protein expression pattern in TNC as compared to TG. Histochemistry studies showed the localization of BKCa channel protein in the perikarya of TG and TNC body cells. The modulatory _2- and _4-subunit was detected in TG and TNC. However, they were more abundant in TNC than in TG. We studied a possible functionality of BKCa channels on CGRP release from TG and TNC in vitro and found that the BKCa channel blocker iberiotoxin caused an increase in CGRP release from the TNC. The response was attenuated by pre-treatment with the BKCa channel opener NS11021. No effect was observed in TG. The findings of the BKCa channel in both vascular and neuronal tissues may suggest a possible role of BKCa channels in the trigeminovascular nociceptive pain pathway and be an advantage in future therapeutic drug development to migraine research. We suggest that a BKCa channel blocker may be used to counteract the vascular dilatation whereas a BKCa channel opener may be effective in the suppression of hyperexcitable sensory neurons.