Office: 317-278-7904
Fax: 317-274-4686
E-mail: johurley@iupui.edu
Research Focus
The Role of Calcium Channels in Migraine
The focus of my research is the role of calcium channels in migraine. It has been recognized for many years that migraine has a genetic component but until 1996 no candidate genes had been identified for this complex disorder. The first report of a gene definitively linked to migraine described a mutation in the P/Q-type calcium channel in patients with Familial Hemiplegic Migraine. Familial Hemiplegic Migraine (FHM) is a rare autosomal dominant form of migraine associated with unusually severe aura symptoms including muscle weakness, hemiplegia and comas sometimes lasting several days. It was hoped that this exciting discovery would pave the way for a better understanding of the pathophysiology of migraine. However, the discovery of a calcium channel linked to migraine was surprising in light of the fact that the newest migraine treatments, such as sumatriptan, are serotonin Type 1 receptor agonists. The relationship between serotonin receptors and calcium channels in migraine is unknown.
Our lab is examining the functional relationships between calcium channels and serotonin receptors in the cells most important in the production of migraine pain. The trigeminal neurons which innervate the cerebral blood vessels and dura are the source of migraine headache. We are using patch-clamp electrophysiology techniques at the single cell level combined with biochemical assays of trigeminal neuron cultures to first characterize the functional relationships between calcium channels and serotonin receptors in normal trigeminal neurons. The primary role of the P/Q-type calcium channel which is highly expressed in nerve terminals of central and peripheral neurons is the control of neurotransmitter release. Activation of neurons leads to the opening of these voltage-dependent channels and the resulting influx of calcium is tightly coupled to neurotransmitter release. Migraine episodes are associated with increased release of a powerful inflammatory neurotransmitter, calcitonin-gene related peptide (CGRP) and the anti-migraine drug sumatriptan returns CGRP to basal levels coincident with headache relief. However, because multiple subtypes of serotonin Type 1 receptors are present in trigeminal neurons on both central and peripheral terminals as well as on cerebral blood vessels, the mechanism and site of action of these drugs is unclear. In addition, the serotonin type 1 receptor agonists, such as sumatriptan are not effective in about 25% of patients and are contraindicated in people with cardiovascular disease or stroke so learning more about the pathophysiology of this disease may lead to better treatments.
The Role of GABA-A Receptors in Alcoholism
Another research project we are currently developing in the laboratory involves examining the role of GABA-A receptors in alcoholism. Recently, our collaborators have reported a strong genetic linkage between variants of GABA-A a2 and g3 subunits and alcohol dependence. GABA-A receptors are pentameric ligand-gated chloride channels which mediate many of the effects of ethanol. The genetic variations seen in the GABA-A a2 and g3 subunits are in non-coding regions, suggesting that these variations may be responsible for subtle alterations in gene expression or splicing patterns. This is perhaps not surprising considering that alcoholism is a complex, multifactorial disease which may be influenced by 20 - 50 different genes. We plan to express various combinations of GABA-A receptor subunits in Xenopus oocytes and compare the characteristics of the channels with voltage clamp electrophysiology. In the planned experiments we will simulate alterations in expression levels by varying the amounts and ratios of injected subunit RNAs and characterizing the biophysical and pharmacological properties of the channels. Protein levels will also be assessed to confirm expression differences. Results obtained from these studies may give us insight into how variations in GABA-A receptor genes may be linked to susceptibility towards alcoholism.
Publications
Hurley, J.H., Bloem, L.J., Pavalko, F., Liu, J., Tian, M., Simon, J.R. and Yu, L. 1998 Structure-function studies of the eighth hydrophobic domain of a serotonin receptor. Journal of Neurochemistry. 72(1):413-421.
Cahill, A.L., Hurley J.H., and Fox, A.P. 1999 Co-expression of cloned a1B, b2a, and a2d subunits produces non-inactivating calcium currents similar to those found in bovine chromaffin cells. Journal of Neuroscience. 20, 1685-1693.
Hurley, J.H., Cahill, A.L., Currie, K.P.M. and Fox, A.P. 2000 The role of dynamic palmitoylation of the b2a subunit in calcium channel inactivation. Proceedings of the National Academy of Sciences USA. 97, 9293-9298.
Hurley, J.H., Zhang, S., Bye, L.S., Marshall, M.S., DePaoli-Roach, A., Guan, K., Fox, A.P.and Yu, L. 2003 Insulin signaling inhibits the 5-HT2C receptor in choroid plexus via MAP kinase. BMC Neuroscience. 4:10.
Hurley, J.H., Cahill, A.L., Wang, M. and Fox, A.P. 2004 Syntaxin 1A regulation of weakly inactivating N-type Ca2+ channels. Journal of Physiology. 560.2, 351-363.