Contact

Department

Cellular and Integrative Physiology

Robert Brenner, Ph.D.

Associate Professor

Education

B.S., University of Texas at Arlington, 1982
M.S., San Diego State University, 1992
Ph.D., University of Texas at Austin, 1997

Research

Our Research Interest
Brenner researchThe focus of our studies has been the large conductance (BK-type) calcium-activated potassium channels. BK channels are gated to open by both micromolar calcium concentrations and voltage. This regulates many voltage-dependent processes that occur coincident with calcium increases, such as regulation of some action potentials, regulation of hormone and neurotransmitter release, and regulation of smooth muscle contractility. While BK channels are encoded by a single gene, they are broadly expressed and have diverse biophysical properties in native cells. This makes these channels an ideal protein for elucidating how ion channel function is regulated to tune the unique electrical properties of individual cells.

Our work has focused on a family of tissue-specific accessory β subunits that interact with the pore-forming α subunit (Figure above), and dramatically alter BK channel biophysical properties in a manner apparently reminiscent of BK channels in native tissues. Our experimental approach is to study these channels in transfected cells using site-directed mutagenesis and patch clamp electrophysiology to understand the biophysical mechanisms that underlies their modulation of BK channels.  We use mouse gene knockouts and physiological studies to understand the relevance of BK β subunit interactions.

Brenner researchPotassium Channel Biophysical Studies
Measuring BK channel open-probability at very negative voltage in the absence and presence of calcium has revealed a Yin-Yang effect of β subunit on BK channel open probability (Figure to right). BK channel β1 and β4 subunits promote channel opening by adjusting the voltage range where the voltage-sensor is activated to more negative potentials (Yin). However, in the absence of voltage-sensor activation β1 and β4 subunits inhibit channel opening by increasing the energetic barrier between the open to closed transition (Yang). As well, β subunits also appear to increase the energetic barrier of open and closed transition states to slow channel opening and closing. Our ongoing studies have been to elucidate that actual molecular interactions between the pore-forming α subunit and the modulatory β subunit that mediate effects on channel open probability and kinetics.

Potassium Channel Regulation of Smooth Muscle Function
Our study of BK β1 knockout mice demonstrated that BK channels are tuned by the smooth muscle specific β1 subunit to sense calcium signals from ryanodine receptors in the sarcoplasmic reticulum (SR). Calcium release from ryanodine receptors is an important feedback signal that mediates relaxation of smooth muscle. BK β1 knockout mice have BK channels that do not adequately respond to calcium release, and we found that the knockouts have increased vascular tone and blood pressure, increases airway smooth muscle constriction and abnormally constricted bladder muscle. Our ongoing studies in airway smooth muscle has allowed us to understand the role of BK and other potassium channels in regulation of airway smooth muscle excitation-Brenner researchcontraction coupling, constriction and control of airflow. Although voltage-dependent calcium channel blockers have long lost favor as bronchodilators for asthma, we have found that human potassium channel polymorphisms do affect asthma severity in individuals, and some potassium channel modulators show promise as bronchodilators. Indeed, an in vitro contraction study of airway shows that the commonly used beta-agonist only partly relaxes airway while a novel potassium channel modulator (Compound X, Figure above) causes a complete and sustained relaxation.

Potassium Channel Regulation of Neuronal Action Potentials
Our studies of BK channels in neurons have focused on the neuron-specific BK β4 subunit. A major finding from our lab is that the slow gating conferred by β4 subunit reduces BK channel contribution to action potential repolarization in hippocampus dentate gyrus granule neurons. Interestingly, knockout β4 appears to result in a faster-gated BK channel and BK gain-of-function. Functional studies indicate that BK channel gain of function paradoxically increases excitability of these neurons and cause seizures. This is consistent with computational modeling studies that indicate that BK sharpening of action potentials, and larger fAHP can reduce activation of other potassium channels that otherwise moderate action potential firing rates. In ongoing studies we are identifying the calcium channels that feed BK channel activation and contribute to seizures. We are also characterizing the adaptive and maladaptive changes of BK channel that follow seizures.

Lab Members

 Vlasislav Bugay
Postdoctoral Fellow

Publications

Lee B, Lee K, Panda S, Gonzales-Rojas R, Chong A, Bugay V, Park HM, Brenner R, Murthy N, Lee HY, Nanoparticle delivery of CRISPR into the brain rescues a mouse model of fragile X syndrome from exaggerated repetitive behaviours, Nature Biomedical Engineering, 2018, in press.

Semenov I, Brenner R. Voltage effects on muscarinic acetylcholine receptor-mediated contractions of airway smooth muscle. Physiol Rep. 2018 Sep;6(17):e13856. doi: 10.14814/phy2.13856. PubMed PMID: 30187663; PubMed Central PMCID: PMC6125245

Barnes EA, Lee L, Barnes SL, Brenner R, Alvira CM, Cornfield DN. β1-Subunit of the calcium-sensitive potassium channel modulates the pulmonary vascular smooth muscle cell response to hypoxia. Am J Physiol Lung Cell Mol Physiol. 2018 Aug 1;315(2):L265-L275. doi: 10.1152/ajplung.00060.2018. Epub 2018 Apr 12. PubMed PMID: 29644895.

Jaffe DB, Brenner R. A computational model for how the fast after hyperpolarization paradoxically increases gain in regularly firing neurons. J Neurophysiol. 2018 Apr 1;119(4):1506-1520. doi: 10.1152/jn.00385.2017. Epub 2018 Jan 10. PubMed PMID: 29357445.

Hu Z, Riquelme MA, Wang B, Bugay V, Brenner R, Gu S, Jiang JX. Cataract-associated connexin 46 mutation alters its interaction with calmodulin and function of hemichannels. J Biol Chem. 2018 Feb 16;293(7):2573-2585. doi: 10.1074/jbc.RA117.001348. Epub 2018 Jan 3. PubMed PMID: 29298900; PubMed Central PMCID: PMC5818178.

Whitmire LE, Ling L, Bugay V, Carver CM, Timilsina S, Chuang HH, Jaffe DB, Shapiro MS, Cavazos JE, Brenner R. Downregulation of KCNMB4 expression and changes in BK channel subtype in hippocampal granule neurons following seizure activity. PLoS One. 2017 Nov 16;12(11):e0188064. doi: 10.1371/journal.pone.0188064. eCollection 2017. PubMed PMID: 29145442; PubMed Central PMCID: PMC5690595.

Wang B, Bugay V, Ling L, Chuang HH, Jaffe DB, Brenner R. Knockout of the BK β4-subunit promotes a functional coupling of BK channels and ryanodine receptors that mediate a fAHP-induced increase in excitability. J Neurophysiol. 2016 Aug 1;116(2):456-65. doi: 10.1152/jn.00857.2015. Epub 2016 May 4. PubMed PMID: 27146987; PubMed Central PMCID: PMC4978790.

Zhang D, Wang X, Wang B, Garza JC, Fang X, Wang J, Scherer PE, Brenner R, Zhang W, Lu XY. Adiponectin regulates contextual fear extinction and intrinsic excitability of dentate gyrus granule neurons through AdipoR2 receptors. Mol Psychiatry. 2017 Jul;22(7):1044-1055. doi: 10.1038/mp.2016.58. Epub 2016 May 3. PubMed PMID: 27137743; PubMed Central PMCID: PMC5491689.

Wang B, Jaffe DB, Brenner R. Current understanding of iberiotoxin-resistant BK channels in the nervous system. Front Physiol. 2014 Oct 9;5:382. doi:10.3389/fphys.2014.00382. eCollection 2014. Review. PubMed PMID: 25346692; PubMed Central PMCID: PMC4190997.

Brenner R. Knockout of the BK β2 subunit reveals the importance of accessorizing your channel. J Gen Physiol. 2014 Nov;144(5):351-6. doi: 10.1085/jgp.201411291. Epub 2014 Oct 13. PubMed PMID: 25311634; PubMed Central PMCID: PMC4210423.

Evseev AI, Semenov I, Archer CR, Medina JL, Dube PH, Shapiro MS, Brenner R. Functional effects of KCNQ K(+) channels in airway smooth muscle. Front Physiol. 2013 Oct 7;4:277. doi: 10.3389/fphys.2013.00277. eCollection 2013. PubMed PMID: 24109455; PubMed Central PMCID: PMC3791379.

Brenner R, Wilcox KS. Potassium Channelopathies of Epilepsy. In: Noebels JL, Avoli M, Rogawski MA, Olsen RW, Delgado-Escueta AV, editors. Jasper’s Basic Mechanisms of the Epilepsies [Internet]. 4th edition. Bethesda (MD): National Center for Biotechnology Information (US); 2012. Available from http://www.ncbi.nlm.nih.gov/books/NBK98143/ PubMed PMID: 22787671.

Semenov I, Herlihy JT, Brenner R. In vitro measurements of tracheal constriction using mice. J Vis Exp. 2012 Jun 25;(64). pii: 3703. doi: 10.3791/3703. PubMed PMID: 22760068; PubMed Central PMCID: PMC3476384.

Petrik D, Wang B, Brenner R. Modulation by the BK accessory β4 subunit of phosphorylation-dependent changes in excitability of dentate gyrus granule neurons. Eur J Neurosci. 2011 Sep;34(5):695-704. doi: 10.1111/j.1460-9568.2011.07799.x. Epub 2011 Aug 16. PubMed PMID: 21848922; PubMed Central PMCID: PMC3168689.

Jaffe DB, Wang B, Brenner R. Shaping of action potentials by type I and type II large-conductance Ca²+-activated K+ channels. Neuroscience. 2011 Sep 29;192:205-18. doi: 10.1016/j.neuroscience.2011.06.028. Epub 2011 Jul 1. PubMed PMID: 21723921; PubMed Central PMCID: PMC3166373.

Semenov I, Wang B, Herlihy JT, Brenner R. BK channel β1 subunits regulate airway contraction secondary to M2 muscarinic acetylcholine receptor mediated depolarization. J Physiol. 2011 Apr 1;589(Pt 7):1803-17. doi: 10.1113/jphysiol.2010.204347. Epub 2011 Feb 7. PubMed PMID: 21300746; PubMed Central PMCID: PMC3099031

Shruti S, Urban-Ciecko J, Fitzpatrick JA, Brenner R, Bruchez MP, Barth AL.The brain-specific Beta4 subunit downregulates BK channel cell surface expression. PLoS One. 2012;7(3):e33429. doi: 10.1371/journal.pone.0033429. Epub 2012 Mar 16. Erratum in: PLoS One. 2012 May;7(5): doi/10.1371/annotation/64524ba8-f739-4fa8-93bf-862b160dca5c. PubMed PMID: 22438928; PubMed Central PMCID: PMC3306404.