ANNA N. BUKIYA, Ph.D.

Associate Professor
Pharmacology

Office: 230K TRANSLATIONAL RESEARCH BUILDING
71 SOUTH MANASSAS
MEMPHIS TN 38163
Tel: (901) 448-2128
abukiya@uthsc.edu

Research Interest/Specialty

The major line of interest in the lab is the lipid regulation of alcohol effect on cerebral circulation at different points during lifetime (from in utero into late adulthood). We are currently pursuing several lines. We are studying the role of dietary cholesterol in the physiology and pathology of cerebral arteries via ion channel involvement. Using rat model of high-cholesterol diet, we were the first to show that dietary cholesterol was a critical nutritional regulator of alcohol-induced constriction of cerebral arteries. After establishing the phenomenon at organ level, we are currently dissecting out molecular and structural mechanisms that enable cholesterol regulation of alcohol-induced constriction of cerebral arteries. Considering that statins - cholesterol lowering therapy - are one of the most widely prescribed and consumed drugs, we are studying their effect on cholesterol level in cerebral artery tissue and on artery response to alcohol.

 

Another line of work is carried out in close collaboration with the Department of Comparative Medicine and with the Department of Obstetrics and Gynecology at UT HSC. This line of work involves non-human primates - baboons, whose pregnancy and developmental milestones are similar to humans. We are focused on the role of endocannabinoid lipids in alcohol effect on fetal cerebral circulation during maternal binge drinking. We are aiming at identification of novel targets of maternal drinking in fetal cerebral arteries. This exploratory work may lay a foundation to early diagnostics and successful prevention/treatment of the fetal alcohol spectrum disorders (FASD) and fetal alcohol syndrome (FAS) that are estimated to affect at least 1% of births in the USA.

   

In addition, we are working on the interaction of potassium (e.g. GIRK, BK) channels with physiologically relevant lipids. In close collaboration with Dr. Alex Dopico (the University of Tennessee Health Science Center), we were able to map several lipid-sensing sites in both BK channel-forming and accessory beta 1 subunits. These studies include recognition motifs for bile acids, cholesterol, and leukotriene B4. We are currently working on developing synthetic ligands for these sites. Newly discovered ligands will be used as lead compounds for designing drugs that modulate diameter of cerebral arteries via action on BK channel. In another collaborative line with Dr. Avia Rosenhouse-Dantsker at the University of Illinois at Chicago we are studying molecular mechanisms of cholesterol modulation of GIRK channels and potential implications of such modulation on GIRK channel physiology and role in Down syndrome pathology.

Curriculum Vitae

Research Keywords

Potassium channel, endocannabinoids, alcohol, cholesterol, fetal alcohol spectrum disorders, statin (atorvastatin), cerebral artery

Selected Reviews and Book chapters

Dopico A., Bukiya A., Singh A. "Steroid regulation of BK channels: of channel protein and surrounding lipids" in Cholesterol Regulation of Ion Channels and Receptors. (2012) I. Levitan and F. Barrantes, editors. Publisher: J. Wiley and sons. pp. 109-134.

Dopico A., Bukiya A., Singh A. (2012) "Differential contribution of BK subunits to nongenomic regulation of channel function by steroids". Pharmacol Ther. 135(2), 133-150.

Dopico AM, Bukiya AN. (2014) Lipid regulation of BK channel function. Front Physiol. 5:312.

Dopico AM, Bukiya AN, Martin GE. (2014) Ethanol modulation of mammalian BK channels in excitable tissues: molecular targets and their possible contribution to alcohol-induced altered behavior. Front Physiol. 5:466.

Bukiya A., Rosenhouse-Dantsker A. "Hypercholesterolemia effect on potassium channels" in Hypercholesterolemia. (2015). In press.

Publications

  1. Bukiya, AN, McMillan, JE, Fedinec, AL, Patil, SA, Miller, DD, Leffler, CW, Parrill, AL, Dopico, AM. Cerebrovascular dilation via selective targeting of the cholane steroid-recognition site in the BK channel β1-subunit by a novel nonsteroidal agent. Mol Pharmacol, 83 (5), 1030-44, 2013.
  2. Bukiya, AN, Patil, SA, Li, W, Miller, DD, Dopico, AM. Calcium- and voltage-gated potassium (BK) channel activators in the 5β-cholanic acid-3α-ol analogue series with modifications in the lateral chain. ChemMedChem, 7 (10), 1784-92, 2012.
  3. Singh, AK, McMillan, J, Bukiya, AN, Burton, B, Parrill, AL, Dopico, AM. Multiple cholesterol recognition/interaction amino acid consensus (CRAC) motifs in cytosolic C tail of Slo1 subunit determine cholesterol sensitivity of Ca2+- and voltage-gated K+ (BK) channels. J Biol Chem, 287 (24), 20509-21, 2012.
  4. Deng, W, Bukiya, AN, Rodríguez-Menchaca, AA, Zhang, Z, Baumgarten, CM, Logothetis, DE, Levitan, I, Rosenhouse-Dantsker, A. Hypercholesterolemia induces up-regulation of KACh cardiac currents via a mechanism independent of phosphatidylinositol 4,5-bisphosphate and Gβγ. J Biol Chem, 287 (7), 4925-35, 2012.
  5. Bukiya, AN, Singh, AK, Parrill, AL, Dopico, AM. The steroid interaction site in transmembrane domain 2 of the large conductance, voltage- and calcium-gated potassium (BK) channel accessory β1 subunit. Proc Natl Acad Sci U S A, 108 (50), 20207-12, 2011.
  6. Bukiya, AN, Vaithianathan, T, Kuntamallappanavar, G, Asuncion-Chin, M, Dopico, AM. Smooth muscle cholesterol enables BK β1 subunit-mediated channel inhibition and subsequent vasoconstriction evoked by alcohol. Arterioscler Thromb Vasc Biol, 31 (11), 2410-23, 2011.
  7. Bukiya, AN, Belani, JD, Rychnovsky, S, Dopico, AM. Specificity of cholesterol and analogs to modulate BK channels points to direct sterol-channel protein interactions. J Gen Physiol, 137 (1), 93-110, 2011.
  8. Bukiya, AN, McMillan, J, Parrill, AL, Dopico, AM. Structural determinants of monohydroxylated bile acids to activate beta 1 subunit-containing BK channels. J Lipid Res, 49 (11), 2441-51, 2008.
  9. Vaithianathan, T, Bukiya, A, Liu, J, Liu, P, Asuncion-Chin, M, Fan, Z, Dopico, A. Direct regulation of BK channels by phosphatidylinositol 4,5-bisphosphate as a novel signaling pathway. J Gen Physiol, 132 (1), 13-28, 2008.
  10. Patil, S, Bukiya, AN, Li, W, Dopico, AM, Miller, D. Design and synthesis of hydroxy-alkynoic acids and their methyl esters as novel activators of BK channels. Bioorg Med Chem Lett, 18 (11), 3427-30, 2008.
  11. Bukiya, AN, Vaithianathan, T, Toro, L, Dopico, AM. The second transmembrane domain of the large conductance, voltage- and calcium-gated potassium channel beta(1) subunit is a lithocholate sensor. FEBS Lett, 582 (5), 673-8, 2008.
  12. Bukiya, AN, Liu, J, Toro, L, Dopico, AM. Beta1 (KCNMB1) subunits mediate lithocholate activation of large-conductance Ca2+-activated K+ channels and dilation in small, resistance-size arteries. Mol Pharmacol, 72 (2), 359-69, 2007.