Alex Dopico, M.D., Ph.D.
Associate Professor

Room 201 Crowe Research Building
adopico@utmem.edu
Phone # (901) 448-3822

Research Interest:

My laboratory is interested in determining the mechanism of action of small amphiphilic compounds on ion channels from excitable cells. One of these amphiphiles is alcohol, the most widely used and abused drug. Some others are physiological modulators, such as bile acids and neurosteroids. Our current research is focused on two projects dealing with large conductance, Ca++-activated K+ (BK) channels. These channel proteins have been demonstrated to be involved in both controlling central neuron excitability and regulating arterial smooth muscle tone. Project 1: To determine the molecular basis for differential actions of alcohol on BK channels from mammalian brain vs. arterial smooth muscle, including modulation of drug action by membrane lipids. Project 2: To determine the structural requirements (both in the amphiphile molecule and the ion channel protein) for the modulation of arterial muscle BK channels by bile acids.

For these studies we combine electrophysiological and molecular biology techniques. Ion channel responses to drug exposure are evaluated in: 1) freshly isolated cells, where we study drug modification of channel behavior in the native environment of the channel protein; 2) isolated patches of cell membrane, where we can address the differential role of different membrane-bound vs. cytosolic second messengers in drug action; 3) artificial bilayers of controlled lipid composition, where we can determine the modulatory role of membrane lipids in drug action.

Ion channel isoforms from relevant tissue are identified. Following mRNA isolation and cloning, channel subunits of known sequence are expressed in heterologous systems such as Xenopus oocytes or HEK-293 cells. Then, we can determine the role of channel subunit composition in drug action by studying drug effects on ion channel complexes that differ in pore-forming and/or modulatory subunit composition. In addition, differential responses to a drug by channels that differ in a given region of a subunit, when studied in the same proteolipid environment, allow us to postulate sites in that subunit for drug recognition. This is probed by studying drug action on expressed channel proteins that include mutations in the postulated region(s).

My laboratory is interested in determining the molecular mechanism of action of alcohol and other small amphiphiles on ion channel proteins from the brain and arterial vessels. To determine the recognition sites for alcohol in these proteins and how alcohol modifies protein function upon interaction with these sites, will provide critical information for understanding how the drug interacts with its targets and, eventually, lead to the design of clinically useful agents to treat conditions associated with alcohol intake.

Selected Recent Publications:

Bukiya AN, Vaithianathan T, Toro L, and Dopico AM. (2008) The second transmembrane domain of the large conductance, voltage- and calcium-gated potassium channel β1 subunit is a lithocholate sensor. Febs Lett. 582:673-8.

Bukiya A, Liu J, Toro L, and Dopico AM. (2007) β1 (KCNMB1)-subunits mediate lithocholate activation of BK channels and dilation in small resistance arteries. Mol. Pharmacol. 72:359-69.

Brodie MS, Scholz A, Weiger TM, and Dopico AM. (2007) Alcohol interactions with calcium-dependent potassium channels. Alcohol. Clin. & Exp. Rsch. 31:1613-17.

Cheng X, Liu J, Asuncion-Chin MT, Blaskova E, Bannister JP, Dopico AM, and Jaggar JH. (2007) A novel CaV1.2 N-terminus expressed in myocytes of resistance size arteries modifies channel regulation by auxiliary subunits. J. Biol. Chem. 282:29211-21.

Dopico AM, and Tigyi G. (2007) A glance at the structural and functional diversity of membrane lipids in Methods to Study Membrane Lipids (Alex Dopico Ed.), The Humana Press, NJ.  

Liu P, Liu J, Asuncion-Chin MT, and Dopico AM. (2006)  CaM kinase II phosphorylation of slo Thr107 regulates activity and ethanol responses of BK channels Nature Neuroscience 9:41-49.

Crowley J, Treistman SN, and Dopico AM. (2005) Distinct structural features of phospholipids differentially determine ethanol sensitivity and basal function of BK channels.  Mol. Pharmacol. 68:4-10. 

Jaggar JH, Li A, Parfenova H, Liu J, Umstot ES, Dopico AM, and Leffler, CW. (2005) Heme is a carbon monoxide receptor for large conductance Ca2+-activated K+ channels.  Circulation Research. 97:805-17. 

Liu P, Xi Q, Ahmed A, Jaggar J, and Dopico, AM. (2004) Essential role for smooth muscle BK channels in alcohol-induced cerebrovascular constriction.  PNAS 101:18217-22.  
 
Liu P, Liu J, Huang W, Li MD, and Dopico AM. (2003) Distinct regions of the slo subunit determine differential BKCa channel responses to ethanol. Alcoholism: Clin. & Exp. Research. 27:1640-44.  

Crowley JJ, Treistman SN, and Dopico AM. (2003) Cholesterol antagonizes ethanol potentiation of human brain BKCa channels reconstituted into phospholipid bilayers. Mol. Pharmacol. 64:365-72.

Dopico AM. (2003) Ethanol sensitivity of BK(Ca) channels cloned from arterial smooth muscle does not require the presence of the beta 1 subunit. Am. J. Physiol. Cell Physiol. 284:C1468-80.

Laboratory roster

Maria T. Asuncion-Chin
Senior Research Assistant
masuncionchi@utmem.edu

Jianxi Liu, Ph.D.
Research Associate
jliu6@utmem.edu

Anna Bukiya , Ph.D.
Postdoctoral Fellow
abukiya@utmem.edu

Thirumalini Vaithianathan, Ph.D.
Postdoctoral Fellow
tvaithia@utmem.edu

Lab phone/fax: (901) 448-1695