Theodore R. Cummins, Ph.D.
Professor of Pharmacology & Toxicology
PhD, Yale University (1996)
Role of voltage-gated sodium channels in excitability and neurological disorders.
My main interest is the biophysics of ion channels and the role of ion channels in neurological diseases. Sodium channel mutations have been linked to several neurological disorders including skeletal muscle non-distrophic myotonias, episodic ataxia and epilepsy. We have shown that mutations in the human skeletal muscle sodium channel, for example, play a crucial role in the development of hyperkalemic periodic paralysis. Changes in the expression and properties of voltage-gated sodium channels are also thought to play important roles in chronic pain. My lab uses electrophysiological, molecular biological and computer modeling techniques to study how specific voltage-gated sodium channels contribute to excitability and to neurological diseases. The long-term goals of my research are to develop a better understanding of the roles that ion channels in play in pathophysiological conditions and to develop strategies for the treatment of neurological disorders that involve ion channels.
Current work in my laboratory is focused on:
A) Understanding the role of peripheral neuronal sodium channels in nociception and neuropathic pain. Specific sodium channels are predominantly expressed in nociceptive sensory neurons. My lab is examining how the activity of these sodium channels are affected by inflammatory mediators and neurotrophins.
B) Investigating the role of sodium channels in genetic diseases. Sodium channel mutations have been identified in patients with epilepsy and skeletal muscle diseases. My lab characterizes the functional consequences of the different disease mutations in heterologous expression systems using patch-clamp techniques. We are also examining the effects of these mutant sodium channels on excitability in neurons and muscle cells.
C) Molecular pharmacology of voltage-gated sodium channels. Several projects focus on understanding the sensitivity of sodium channels to specific pharmacologic agents. Identify local anesthetics and anticonvulsants that preferentially target sodium channels involved in pain sensations. Identify the molecular determinants of sodium channel sensitivity to pore blockers. Identify biological toxins from marine cone snail and tarantula venoms that specifically target voltage-gated sodium channels. These studies will provide information on the pharmacology of specific voltage-gated sodium channels that are thought to play important roles in epilepsy and pain and hopefully will contribute to the development of better treatments for these neurological disorders.
Cummins TR, Sheets PL, Waxman SG. The roles of sodium channels in nociception: Implications for mechanisms of pain. Pain. 2007 Oct;131(3):243-57.
Sheets PL, Jackson JO 2nd, Waxman SG, Dib-Hajj SD, Cummins TR. A Nav1.7 channel mutation associated with hereditary erythromelalgia contributes to neuronal hyperexcitability and displays reduced lidocaine sensitivity. J Physiol. 2007 Jun 15;581(Pt 3):1019-31.
Smith JJ, Cummins TR, Alphy S, Blumenthal KM. Molecular interactions of the gating modifier toxin ProTx-II with NaV 1.5:implied existence of a novel toxin binding site coupled to activation. J Biol Chem. 2007 Apr 27;282(17):12687-97.
Rush AM, Cummins TR, Waxman SG. Multiple sodium channels and their roles in electrogenesis within dorsal root ganglion neurons. J Physiol. 2007 Feb 15;579(Pt 1):1-14.
Sheets PL, Gerner P, Wang CF, Wang SY, Wang GK, Cummins TR. Inhibition of Nav1.7 and Nav1.4 sodium channels by trifluoperazine involves the local anesthetic receptor. J Neurophysiol. 2006 Oct;96(4):1848-59.
Rush AM, Dib-Hajj SD, Liu S, Cummins TR, Black JA, Waxman SG. (2006).
A single sodium channel mutation produces hyper- or hypoexcitability in different types of neurons. Proc. National Academic Science USA, 103(21):8245-50.
Amir R, Argoff CE, Bennet GJ, Cummins TR, Durieux ME, Gerner P, Gold MS, Porreca F, Strichartz GR. (2006). The role of sodium channels in chronic inflammatory and neuropathic pain. Journal of Pain, 7:S1-29.