Wnt/ß-catenin mediates alcohol molecular tolerance regulating BK channel surface expression
Institute of Neurobiology, University of Puerto Rico Medical Sciences Campus, San Juan, Puerto Rico
PI Name: Cristina Velázquez, Ph.D.
According to the National Institute of Alcohol Abuse and Alcoholism, Hispanics who choose to drink are more likely to consume higher volumes of alcohol and develop alcoholism than non-Hispanic Whites. Our work focuses on developing novel pharmacological approaches to prevent and treat alcohol misuse to mitigate its negative impact on individuals and society. Alcohol tolerance, defined as the decrease in effect of alcohol in spite of unaltered concentration is recognized by the Diagnostic and Statistical Manual of Mental Disorders (DSM) as a primary step for escalating intake leading from abuse to dependency in humans. Whether an individual develops drug dependency and addiction is a function of both genetic predisposition and environmental factors. The large conductance voltage- and calcium-activated channel (BK) is a key regulator of neuronal excitability and has been genetically associated to behavioral alcohol tolerance in invertebrates. In mammals the molecular structure of BK channels is complex and composed of alpha and beta subunits, which alter expression and function of the channel in response to ethanol. Different isoforms of the BK channel show variations in alcohol sensitivity. These differences have been linked to alcohol tolerance and increased voluntary consumption. The regulatory mechanisms orchestrating both translation and surface expression of these isoforms in response to ethanol is not well understood and likely underlies the cellular adaptations to long term alcohol misuse.
We have recently uncovered the role of a key pathway activated by ethanol exposure, which regulates changes in BK channel surface expression involved in persistent forms of alcohol tolerance. The canonical Wnt/ß-catenin pathway regulates BK channel surface expression in a protein synthesis-dependent manner. This key regulatory pathway has been the focus of intense study in the field of cancer research and thus affords us clinically tested drugs for future studies which can be applied with the novel intent of preventing and treating alcohol dependency.
Center for Biomedical Research Excellence (COBRE) Project P.I. award to Cristina Velázquez, Ph.D. - January 2015. Title: Alcohol Tolerance via Wnt/ß-catenin impacts BK expression and subsequent ethanol consumption.
Public Health Impact Statement
Alcoholism is a devastating disease that affects millions of individuals and their families excising an enormous toll on society. The Centers for Disease Control and Prevention has estimated the overall economic cost alone attributable to alcohol use and alcohol-use disorders is significantly higher than that for tobacco or illicit drug use, rounding at $236 billion a year. Alcohol tolerance is a key step towards escalating alcohol consumption and subsequent dependence, which particularly impacts Hispanic communities. Our research aims to make significant contributions towards novel, therapeutic approaches to prevent and treat alcohol misuse by understanding the molecular underpinnings of alcohol tolerance.
Grant Support (all grant numbers)
RCMI grant G12 RR; U54 RR. Imaging core at the Institute of Neurobiology: NSF Grant DBI-0115825 and DoD Grant 52680-LS-IS. MBRS-RISE Fellowship awarded to Stephanie Palacio. R01 A8380110 awarded to Dr. Steven Treistman: miRNA Regulation of Gene Expression in Alcohol Tolerance and Withdrawal. Project P.I. COBRE awarded to Dr. Cristina Velázquez A8380115: Alcohol Tolerance via Wnt/ß-catenin Impacts BK Expression and Subsequent Ethanol Consumption.
Publication Citation and Link (if applicable)
- Time-dependent effects of ethanol on BK channel expression and trafficking in hippocampal neurons. Stephanie Palacio1,2, Cristina Velázquez-Marrero1, Garrett E. Seale1 , Guillermo A. Yudowski1,2 , Steven N. Treistman1,2 (2015). (Accepted pending revision) Alcoholism: Clinical and Experimental Research.
- Lipids modulate the increase of BK channel calcium sensitivity by the β1 subunit. Yuan C, Velázquez-Marrero C, Bernardo A, Treistman SN. PLoS One. 2014 Sep 25;9(9):e107917. doi: 10.1371/journal.pone.0107917. eCollection 2014.
- Large conductance voltage- and Ca2+-gated potassium (BK) channel β4 subunit influences sensitivity and tolerance to alcohol by altering its response to kinases. Velázquez-Marrero C, Seale GE, Treistman SN, Martin GE. J Biol Chem. 2014 Oct 17;289(42):29261-72. doi: 10.1074/jbc.M114.604306. Epub 2014 Sep 4.
- μ-Opioid inhibition of Ca2+ currents and secretion in isolated terminals of the neurohypophysis occurs via ryanodine-sensitive Ca2+ stores. Velázquez-Marrero C, Ortiz-Miranda S, Marrero HG, Custer EE, Treistman SN, Lemos JR. J Neurosci. 2014 Mar 5;34(10):3733-42. doi: 10.1523/JNEUROSCI.2505-13.2014.
- Modulation/physiology of calcium channel sub-types in neurosecretory terminals. Lemos JR, Ortiz-Miranda SI, Cuadra AE, Velázquez-Marrero C, Custer EE, Dad T, Dayanithi G. Cell Calcium. 2012 Mar-Apr;51(3-4):284-92. doi: 10.1016/j.ceca.2012.01.008. Epub 2012 Feb 17. Review.
- The relationship between duration of initial alcohol exposure and persistence of molecular tolerance is markedly nonlinear. Velázquez-Marrero C, Wynne P, Bernardo A, Palacio S, Martin G, Treistman SN. J Neurosci. 2011 Feb 16;31(7):2436-46. doi: 10.1523/JNEUROSCI.5429-10.2011.
- Differential modulation of N-type calcium channels by micro-opioid receptors in oxytocinergic versus vasopressinergic neurohypophysial terminals. Ortiz-Miranda SI, Dayanithi G, Velázquez-Marrero C, Custer EE, Treistman SN, Lemos JR. J Cell Physiol. 2010 Oct;225(1):276-88. doi: 10.1002/jcp.22263.
- Voltage-dependent kappa-opioid modulation of action potential waveform-elicited calcium currents in neurohypophysial terminals. Velázquez-Marrero CM, Marrero HG, Lemos JR. J Cell Physiol. 2010 Oct;225(1):223-32. doi: 10.1002/jcp.22247.
- ATP elicits inward currents in isolated vasopressinergic neurohypophysial terminals via P2X2 and P2X3 receptors. Knott TK, Velázquez-Marrero C, Lemos JR. Pflugers Arch. 2005 Sep;450(6):381-9. Epub 2005 Jun 30.
- Ca2+ syntillas, miniature Ca2+ release events in terminals of hypothalamic neurons, are increased in frequency by depolarization in the absence of Ca2+ influx. De Crescenzo V, ZhuGe R, Velázquez-Marrero C, Lifshitz LM, Custer E, Carmichael J, Lai FA, Tuft RA, Fogarty KE, Lemos JR, Walsh JV Jr. J Neurosci. 2004 Feb 4;24(5):1226-35.
- A Burgos, C Velázquez-Marrero and SN Treistman. Quantification of ß-catenin in response to 25mM ethanol. 2014 Salud Itegral; Enlazando Ciencia y Sociedad Foro Annual de Investigación y Educación. Recinto de Ciencias Médicas, UPR.
- C Velázquez-Marrero, A Bernardo, G Seale, J García, S Palacio, and SN Treistman. Molecular tolerance of the BK channel after 6hr alcohol exposure is protein synthesis dependent. 2011 Neuroscience Meeting Planner. Washington, DC: Society for Neuroscience, 2011. Online.
- S Palacio, GE Seale, C Velázquez-Marrero, SN Treistman, GA Yudowski (2011). Internalization of BK channels in HEK cells after chronic exposure to ethanol. 2011 Salud Itegral; Enlazando Ciencia y Sociedad 31er Foro Annual de Investigación y Educación. Recinto de Ciencias Médicas, UPR.