The focus of my research career has been the study of ion channels in order to acquire a comprehensive understanding on how they operate and study their involvement in human diseases known as channelopathies.

1- CLONING NAV1.5 THE CARDAIC SODIUM CHANNEL AND ITS LINK TO SEVERAL CONGENITAL ARRHYTHMIC DISORDERS.

We were the first to clone and characterize the human cardiac sodium channel, known now as NaV1.5. This was an important step toward understanding the link of this channel to cardiac arrhythmias. We are recognized internationally for our studies on channelopathies and, together with key collaborators, have unravelled several molecular mechanisms involved in long QT syndrome, Brugada syndrome, and atrial fibrillation and several neuromuscular disorders. We have recently discovered a novel cardiac channelopathy, Indeed we were the first to implicate omega currents in cardiac arrhythmias associated with dilated cardiomyopathy (DCM).
• Gosselin-Badaroudine P., Keller D.I., Huang H, Pouliot V., Chatelier A, Osswald S, Brink M, and Chahine M. (2012): A proton leak current through the cardiac sodium channel is linked to mixed arrhythmia and the dilated cardiomyopathy phenotype. PlosONE , 7(5):e38331.
• Chang C.C., Acharfi S., Chiang F.T., Wu M.H., Sung T.C., Chahine M. (2004). A novel mutation on SCN5A gene manifests as a malignant form of long QT syndrome with perinatal onset of sinus bradycardia, atrioventricular block and ventricular tachycardia. Cardiovasc Res. 64(2):268-78.
• Baroudi G., Pouliot V., Denjoy I., Guicheney P., Shrier A., Chahine M. (2001). Novel mechanism for Brugada syndrome: defective surface localization of an SCN5A mutant (R1432G). Circ Res. 88:E78-E83.
• M.E., George A.L., Jr., Chen L.Q., Chahine M., Horn R., Barchi R.L., Kallen R.G. (1992). Primary structure and functional expression of the human cardiac tetrodotoxin-insensitive voltage-dependent sodium channel. Proc Natl Acad Sci USA. 89:554-558.

2- UNRAVELING THE MOLECULAR PHARMACOLOGY OF NAV1.5 CHANNEL

We have unraveled the molecular mechanism of action several local anesthetics and antiarrhythmic drugs on NaV1.5, the human heart sodium channel.
• Poulin H, Bruhova I., Timour Q., Theriault O, Beaulieu J-M., Frassati D., and Chahine M. (2014) Fluoxetine Blocks Nav1.5 Channels Via a Mechanism Similar to That of Class 1 Antiarrhythmics. Molecular Pharmacology, 86(4):378-89.
• O'Leary M.E., Digregorio M., Chahine M. (2003). Closing and inactivation potentiate the cocaethylene inhibition of cardiac sodium channels by distinct mechanisms. Mol Pharmacol. 64:1575-1585.
• O'Leary M.E., Chahine M. (2002). Cocaine binds to a common site on open and inactivated human heart (NaV1.5) sodium channels. J Physiol. 541:701-716.
• Marcotte P., Chen L.Q., Kallen R.G., Chahine M. (1997). Effects of Tityus serrulatus scorpion toxin gamma on voltage-gated Na+ channels. Circ Res. 80:363-369.

3- UNRAVELING THE ROLE OF NAV1.4 THE SKELETAL MUSCLE SODIUM CHANNL IN NEUROMUSCULAR DISORDERS

Pioneer studies on NaV1.4, the skeletal muscle sodium channel have yielded novel insight into the genetic causes of paramyotonia congenital, a debilitating disease of skeletal muscle. My studies were among the first to employ molecular approaches to investigate the role of the S4 voltage sensor in sodium channel gating. The data showed that a group of well-defined arginine residues of the voltage sensor were specifically linked to sodium channel inactivation.
In collaboration with my colleagues in France we have demonstrated that a severe loss of function of NaV1.4 at the neuromuscular junction causes myastenic syndrome. We have identified and biophysically characterised a NaV1.4 founder mutation associated with cold-induced myotonia in French Canadians. We have recently unraveled the structure of NaV1.4 sodium channel voltage sensors. These structural insights of Na+ channels that we provided are crucial for the physiology of membrane excitability, the pathophysiology of cardiac arrhythmias, and future drug development.
• Habbouti K., Guiliano S., Poulin H., Sternberg D., Eymard B., Rivier F., Moraled J.R., Chahine M., Nicole S., Bendahhou S. (2016) Recessive skeletal muscle sodium channel mutations underlay congenital myasthenic syndrome-like phenotype. Neurology 2016 Jan 12;86(2):161-169.
• Zhao J, Dupré N, Puymirat J, Chahine M. (2012) Biophysical characterization of M1476I, a founder mutation associated with cold-induced myotonia in French Canadians. J. Physiol. (London) Jun 1; 590(Pt 11):2629-44.
• Gosselin-Badaroudine P., Delemotte L., Moreau A., Klein M.L., and Chahine M. (2012) Gating pore currents and the structural resting state of Nav1.4 voltage sensor domains. Proc Natl Acad Sci USA. 109(47):19250-5.
• Chahine M., George A.L., Jr., Zhou M., Ji S., Sun W., Barchi R.L., Horn R. (1994). Sodium channel mutations in paramyotonia congenita uncouple inactivation from activation. Neuron. 12:281-294.

4- UNRAVELING THE ROLE OF PERIPHERAL SODIUM CHANNELS, THEIR PHYSIOLOGY, PARMACOLOGY AND THEIR REGULATION BY AUXILARY SUBUNITS

Several years ago we have initiated a project on the physiology and the pharmacology of NaV1.7 and NaV1.8, two peripheral nerve sodium channels. We have published several papers on the subject. We studied the effects of PKA and PKC on these channels. We discovered that PKC-epsilon modulates NaV1.8 sodium channels. We studied the effect of the regulatory subunits known to associate with sodium channels. Indeed, the role of NaV channels in nociception depends on modulation by various auxiliary factors such as auxiliary beta-subunits and cytoskeletal proteins and the phosphorylation states of the neurons. In addition, we were invited to write a review on the subject in TRENDS in Pharmacological Sciences. The review describes the modulation of NaV sensory neurons by various auxiliary beta-subunits, protein kinases and cytoskeletal proteins. Here are some highlights
• Vijayaragavan K., O'Leary M.E., Chahine M. (2001). Gating properties of Nav1.7 and Nav1.8 peripheral nerve sodium channels. J Neurosci. 21:7909-7918.
• Vijayaragavan K., Boutjdir M., Chahine M. (2004). Modulation of nav1.7 and nav1.8 peripheral nerve sodium channels by protein kinase A and protein kinase C. J Neurophysiol. 91:1556 1569.
• Chatelier A., Dahllund L., Eriksson A., Krupp J., and Chahine M. (2008) Biophysical characterizations of human Nav1.7 splice variants and their regulation by Protein Kinase A. Journal of Neurophysiology 99(55):2241-2250.
• Chahine M., K. Vijayaragavan & Y. Okamura (2005). Regulation of Nav channels in sensory neurons. Trends Pharmacol Sci. 26(10):496-502.

5- INDENTIFYING A NOVEL CLASS OF CALCIUM CHANNELS.

Insect DSC1 for Drosophila sodium channel 1 has a sequence that is intermediate between voltage-gated sodium and calcium channels, but have hitherto been classified as the former. We. cloned and characterize honeybee DSC1, revealing high selectivity for Ca2+ and suggesting reclassification of DSC1 homologs as Ca2+ channels that we named CaV4.
• Gosselin-Badaroudine P, Moreau A, Simard L, Cens T, Rousset M, Collet C, Charnet P, Chahine M. Biophysical characterization of the honeybee DSC1 orthologue reveals a novel voltage-dependent Ca2+ channel subfamily: CaV4. J Gen Physiol. 2016 Aug;148(2):133-45.