The primary research interests of our laboratory are how ion channels regulate the electrical excitability of cells and how defects in these channels lead to human disease.
Electrical signaling is a fundamental mechanism by which cells initiate and regulate contraction of muscles, beating of the heart, secretion of hormones, and communication among neurons. Ion channels contribute a crucial component of the machinery to accomplish this signaling by forming pores in the cell membrane to allow the passage of electric current. In the past decade, mutations of ion channel genes have been found to be the primary cause for over 30 human diseases.
Those of neurologic interest include periodic paralysis, myotonia, familial migraine, episodic ataxia, cerebellar ataxia, and some forms of epilepsy. We have been studying the functional consequences of mutations in sodium, calcium, and chloride channels that have been linked to muscle disorders causing episodic paralysis or stiffness (myotonia).
Patch-clamp recordings in muscle cultured from patients or from expression of mutant channels have revealed defects in channel gating (opening and closing) or a reduction in the level of channel expression. A combination of animal-based and computer models are used to explore the implications of these channel defects on muscle excitability, and thereby gain insights on the fundamental cause of patients’ symptoms. This approach has advanced our understanding of episodic disorders of the nerve and muscle tremendously and led to new approaches toward ameliorating these conditions.
Wu, F.F., et al., A Sodium Channel Knock-In Mutant (NaV1.4-R669H) Mouse Model of Hypokalemic Periodic Paralysis. Journal of Clinical Investigation, 2011. 121(10): p. 4082-4094.
Francis, D.G., et al., Leaky sodium channels from voltage sensor mutations in periodic paralysis, but not paramyotonia. Neurology, 2011. 76(19): p. 1635-41.
Cannon, S.C., Voltage-sensor mutations in channelopathies of skeletal muscle. J Physiol, 2010. 588(Pt 11): p. 1887-95.
Hayward, L.J., et al., Targeted mutation of mouse skeletal muscle sodium channel produces myotonia and potassium-sensitive weakness. J Clin Invest, 2008. 118(4): p. 1437-1449.
Struyk, A.F. and Cannon, S.C., A Na+ Channel Mutation Linked to Hypokalemic Periodic Paralysis Exposes a Proton-selective Gating Pore. J Gen Physiol, 2007. 130(1): p. 11-20.