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Andrea L. Meredith, PhD

Academic Title:

Associate Professor

Primary Appointment:

Physiology

Location:

655 W. Baltimore Street BRB, 5-011

Phone (Primary):

410-706-5991

Fax:

410-706-8341

Education and Training

Postdoc, Stanford University (2000-2006).
Studied the function and physiological role of BK potassium ion channels in the lab of Dr. Richard Aldrich.

Ph.D. in Neuroscience, The University of Texas Southwestern Medical School (2000).
Studied neuronal specification and differentiation, focusing on Mash1, a neural-specific basic helix-loop-helix transcription factor in the lab of Dr. Jane Johnson.

Highlighted Publications

Bailey, CS, Moldenhauer, HJ, Park, SM, Keros, S, and Meredith, ALKCNMA1-Linked Channelopathy (In Press- the Journal of General Physiology)

Plante, AE, Moldenhauer, H, Harvey, JRM, and Meredith, AL (2019). Gain-of-Function Effects of KCNMA1-N999S Mutation on Human BK K+ Channel Properties. Biophysical Society Abstract.

Plante, A, Lai, MH, Lu, J, and Meredith, AL. Effects of single nucleotide polymorphisms in human KCNMA1 on BK current properties. Under Review.

McNally, BA, Plante, AE, and Meredith, AL. Diurnal properties of voltage-gated Ca2+ currents in SCN and roles in action potential firing. Journal of Physiology, In Press.

Zhang, J, Guan, X, Li, Q, Meredith, AL, Pan, HL, and Yan, J (2018). Glutamate-activated K+ signaling complexes formed by BK channels and NMDA receptors. PNAS 115(38):E9006-E9014.

Nelson, A.B., Faulstich, M., Moghadam, S., Onori, K., Meredith, AL, and du Lac, S (2017). BK channels are required for multisensory plasticity in the oculomotor system. Neuron 93(1):211-220. PMCID:  PMC5575767

Whitt, JP, McNally, BA, and Meredith, AL (2018). Differential contribution of Ca2+ sources to day and night BK current activation in the circadian clock. Journal of General Physiology 15(2): 259-275. PMCID:  PMC5806683
-This article was featured in JGP’s Research News: ‘Up all night: BK channels’ circadian dance with different calcium sources.’ JGP 150(2):175.

Whitt, JP, Montgomery, JR, and Meredith, AL (2016). BK channel inactivation gates daytime excitability in the circadian clock. Nature Communications 7:10837. PMCID: PMC4785228

Shelley, C, Whitt, JP, Montgomery, JM, and Meredith, AL (2013). Phosphorylation of a constitutive serine inhibits BK channel variants containing the alternate exon ‘SRKR’. Journal of General Physiology 142 (6):585-598.  PMCID:  PMC3840924
*Highlighted in commentary: Multilevel regulation: Controlling BK channels in central clock neurons. JGP 142(6): 579-583.

Montgomery, JM, Whitt, JP, Wright, BN, Lai, ML, and Meredith, AL (2013). Mis-expression of the BK K+ channel disrupts suprachiasmatic nucleus rhythmicity and alters clock-controlled behaviors. American Journal of Physiology- Cell Physiology304(4):C299-C311. PMCID: PMC3566534

Meredith, AL, Wiler, SW, Miller, BH, Takahashi, JS, Fodor, AA, Ruby, NF, and Aldrich, RW (2006). BK calcium-activated potassium channels regulate circadian behavioral rhythms and pacemaker output.  Nature Neuroscience 9(8):1041-1049. PMCID: PMC2909323
* Highlighted in News and Views (Nat. Neurosci. 9:985-986, 2006).

Book chapters: Genetic methods for studying ion channel function in physiology and disease (Ch. 13) and Alternative splicing (Ch. 37). Handbook of Ion Channels. Taylor and Francis, CRC Press, Boca Raton, FL.

Additional Publication Citations

Alshahrani, S, Rapoport, RM, Zahedi, K, Jiang, M, Nieman, M, Barone S, Meredith AL, Lorenz JN, Rubinstein J, and Soleimani M (2017). The Non-Diuretic Hypotensive Effects of Thiazides Are Enhanced During Volume Depletion StatesPLoS One.  2017 Jul 18;12(7).  eCollection 2017.  PMCID: PMC5515454

Wang W, Zhang X, Gao Q, Lawas M, Yu L, Chen X, Gu M, Sahoo N, Li X, Ireland S, Meredith AL, Xu H (2017). A voltage-dependent K+ channel in the lysosome is required for refilling lysosomal Ca2+ storesJournal of Cell Biology 216(6):1715-1730. PMCID:  PMC5461029

Nelson, A.B., Faulstich, M., Moghadam, S., Onori, K., Meredith, AL, and du Lac, S (2017). BK channels are required for multisensory plasticity in the oculomotor systemNeuron 93(1):211-220.

Nagaraj, C, Tang, B, Nagy, BM, Papp, R, Jain, JP, Marsh, LM, Meredith, AL, Ghanim, B, Klepetko, W, Kwapiszewska, G, Weir, EK, Olschewski, H, Olschewski, A (2016). DHA causes rapid pulmonary arterial relaxation via KCa channel-mediated hyperpolarization in pulmonary hypertensionEuropean Respiratory Journal 48(4):1127-1136. PMCID:  PMC5470640

Whitt et al, Nature Communications, 2016 highlighted in 22 online news stories: https://nature.altmetric.com/details/6052573/news.  ‘Brain Study May Shed Light On How We Fall Asleep And Wake Up,’ Huffington Post, April 19, 2016: 

Singh H, Li M, Hall L, Chen S, Sukur S, Lu R, Caputo A, Meredith AL, Stefani E, Toro L (2016). MaxiK channel interactome reveals its interaction with GABA transporter 3 and heat shock protein 60 in the mammalian brain. Neuroscience 317:76-107. PMCID: PMC4737998

White RS, Zemen BG, Khan Z, Montgomery JR, Herrera GM, Meredith AL. (2015) Evaluation of mouse urinary bladder smooth muscle for diurnal differences in contractile properties. Front Pharmacol. Jan 9;5:293.  PMCID: PMC4288323

Lai MH, Wu Y, Gao Z, Anderson ME, Dalziel JE, Meredith AL. (2014) BK channels regulate sinoatrial node firing rate and cardiac pacing in vivo. Am J Physiol Heart Circ Physiol. Nov 1;307(9):H1327-38.  PMCID: PMC4217012

Li B, Jie W, Huang L, Wei P, Li S, Luo Z, Friedman AK, Meredith AL, Han MH, Zhu XH, Gao TM.  (2014)  Nuclear BK channels regulate gene expression via the control of nuclear calcium signaling.  Nature Neuroscience 2014 Aug;17(8):1055-63. PMCID: PMC4115017

Hermanstyne TO, Subedi K, Le WW, Hoffman GE, Meredith AL, Mong JA, Misonou H.  (2013)  Kv2.2: a novel molecular target to study the role of basal forebrain GABAergic neurons in the sleep-wake cycle.  Sleep. 36(12):1839-48.  PMCID: PMC3825433

Singh H, Lu R, Bopassa JC, Meredith AL, Stefani E, Toro L.  (2013)  MitoBK(Ca) is encoded by the Kcnma1 gene, and a splicing sequence defines its mitochondrial location.  Proceedings of the National Academy of Sciences 110(26):10836-41.  PMCID: PMC3696804

Singh, H, Lu, R, Bopassa, JC, Meredith, AL, Stefani, E, and Toro, L (2013). Cardiac mitoBKCa K+ Channel is Encoded by Kcnma1 Gene and a Splicing Sequence Defines its Mitochondrial Location. Proceedings of the National Academy of Sciences 110(26):10836-41. PMCID: PMC3696804.

Maison, SF, Pyott, SJ, Meredith, AL, and Liberman, MC (2013). Olivocochlear suppression of outer hair cells in vivo: evidence for combined action of BK and SK2 channels throughout the cochlea. American Journal of Neurophysiology 109(6):1525-1534. PMCID: PMC3602942.

Wahyu, ID, Kamasawa, N, Matsui, K, Meredith, AL, Watanabe, M, and Shigemoto, R (2013). Quantitative localization of Cav2.1 (P/Q-type) voltage-dependent calcium channels in Purkinje cells: somatodendritic gradient and distinct somatic co-clustering with calcium-activated potassium channels. Journal of Neuroscience 33(8):3668-3678. PMCID: In Progress.

Montgomery, JM and Meredith, AL. (2012). Genetic activation of BK currents in vivo generates bi-directional effects on neuronal excitability. Proceedings of the National Academy of Sciences 109 (46): 18997-19002. PMCID: PMC3503162

Montgomery, JM and Meredith, AL (2012). Genetic activation of BK currents in vivo generates bi-directional effects on neuronal excitability. PNAS 109(46):18997-9002.  PMCID: PMC3503162

Montgomery, JM, Whitt, JP, Wright, BN, Lai, ML, and Meredith, AL (2012). Mis-expression of the BK K+ channel disrupts suprachiasmatic nucleus circuit rhythmicity and alters clock-controlled behavior. AJP- Cell Physiol. [ePublished ahead of print Nov. 21, 2012].  PMCID: PMC3566534

Herrera, GM and Meredith, AL (2010).  Diurnal variation in urodynamics of rat. PLOS One 5(8): e12298.   PMCID:  PMC2924395

Girouard H, Bonev AD, Hannah, RM, Meredith AL, Aldrich RW and Nelson MT. Astrocytic endfoot Ca2+ and BK channels determine both arteriolar dilation and constriction.  PNAS 107(8):3811-6.  PMCID: PMC2840528

Imlach WL, Finch SC, Miller JH, Meredith AL, Dalziel JE, (2010) A Role for BK Channels in Heart Rate Regulation in Rodents. PLoS One 5(1): e8698.  PMCID: PMC2806827

Kent, J and Meredith, AL (2008).  BK channels regulate spontaneous action potential rhythmicity in the suprachiasmatic nucleus.PLOS One 3(12):e3884.  PMCID: PMC2586654

Imlach, WL, Finch, SC, Dunlop, J, Meredith, AL, Aldrich, RW, and Dalziel, JE (2008).  The molecular mechanism of ‘ryegrass staggers,’ a neurological disorder of potassium channelsJ Pharmacol Exp Ther.327:657-664.

Pyott, SJ, Meredith, AL, Fodor, AA, Yamoah, EN, and Aldrich, RW (2007).  Normal cochlear function in mice lacking the BK channel alpha, beta-1 or beta-4 subunits. JBC. 282(5): 3312-3324.

Filosa, JA, Bonev, AD, Straub, SV, Meredith, AL, Wilkerson, MK, Aldrich, RW, and Nelson, MT (2006).  Local potassium signaling couples neuronal activity to vasodilation in the brain.  Nature Neuroscience 9(11): 1397-1403.

Misonou, H, Menegola, M, Buchwalder, L, Park, EW, Meredith, AL, Rhodes, KJ, Aldrich, RW, and Trimmer, JS (2006). Localization of the BK Ca2+-activated K+ channel Slo1 in axons and nerve terminals in mammalian brain and cultured neuronsJ Comp Neurol. 496:289-302.

Meredith, AL, Thorneloe, KS, Werner, ME, Nelson, MT, and Aldrich, RW (2004).  Overactive bladder and incontinence in the absence of the BK Ca2+- activated K+ channel. Journal of Biological Chemistry 279:36746-36752.

Meredith, AL and Johnson, JE (2000). Negative autoregulation of MASH1 expression in CNS developmentDevelopmental Biology 222: 336-346.

Horton, S, Meredith, AL, Richardson, JA, and Johnson, JE (1999). Correct coordination of neuronal differentiation events in ventral forebrain requires the bHLH factor MASH1Molecular and Cellular Neuroscience 14: 355-369.

Boluyt, MO, O'Neill, LO, Bing, OHL, Meredith, Al, Crow, MT, and Lakatta, EG (1994). Alterations in cardiac gene expression during the transition from stable hypertrophy to heart failure. Circulation Research 75(1): 23-32.

Research Interests

We are interested in how specific ion channels influence information coding at the membrane, cellular, circuit/organ, and whole animal levels. We study a unique ion channel, the large conductance, Ca2+-activated K+ channel (BK). BK channels are allosterically regulated by voltage and Ca2+ and play prominent roles in neuronal and muscle physiology, modulating action potential repolarization, afterhyperpolarizations, and repetitive firing. Although BK channels have been extensively studied at the biophysical level, less is known about their roles in non-excitable cell types or intact physiological systems. In my lab, we combine the genetic manipulation of ion channels with electrophysiology and behavior. I made a deletion of the BK channel alpha subunit in mouse (Slo-/- or Kcnma1-/-).

KCNMA1-Linked Channelopathy

In people, mutations in KCNMA1, the gene that encodes the pore-forming subunit of the BK channel, have been linked to seizures, paroxysmal dyskinesia, and other types of neuromuscular and neurological dysfunction.  We are studying how human genetic variation (pathological mutations and single nucleotide polymorphisms) influence neuronal firing patterns and brain and motor function.  Our first priority is to understand how clinical symptoms are produced by the changes in BK channel activity associated with patient mutations.  Find out more about this new, very rare KCNMA1-linked channelopathy here.

Identifying novel roles for BK channels

BK channels are highly expressed in subsets of central neurons and smooth muscle, and are also present in skeletal muscle, neuroendocrine tissues, peripheral neurons, and kidney. Unlike the voltage-gated K+ channel family, there is only one gene that encodes the BK channel, and Kcnma1-/- mice display a surprising number of phenotypes at the cellular and behavioral levels. This lack of compensation or redundancy has enabled us to use the BK channel deletion mouse as a general mechanism for perturbing signaling in a variety of pathways. To identify new systems in which BK channels play dominant roles, we are conducting phenotypic screens in Kcnma1-/- mice with global and tissue-specific conditional deletions of the BK channel.

BK channels regulate excitability in the brain's intrinsic clock

Circadian physiology is an ideal model system for studying information coding. Daily behavioral and physiological rhythms (~ 24 hrs) are a universal trait of animals, vital for adaptation to their environment and overall fitness. In mammals, lesion and transplantation studies have localized the principal circadian pacemaker to the suprachiasmatic nucleus (SCN) of the hypothalamus, identifying a discrete neural substrate for a complex behavior. Individual SCN neurons exhibit daily oscillations in spontaneous action potential firing. My lab studies how the daily variation in spontaneous firing rate is generated and how patterns of SCN activity confer circadian timing to behaviors. We recently identified a role for Kcnma1, the gene that encodes the BK Ca2+-activated K+ channel, in pacemaker function. Kcnma1-/- mice have degraded circadian behavioral and physiological rhythms, and their SCN neurons exhibit aberrant daily action potential rhythms.

Research Images

 

Awards and Affiliations

  • 2018 Molecular Devices Women in Science Award for registration at the Ion Channels Gordon Research Conference at Mt. Holyoke, MA.
  • S&R Foundation Ryuji Ueno Award for Ion Channels or Barrier Function Research (2011) - The American Physiological Society
  • Maryland Outstanding Young Scientist of the Year (2008) - The Maryland Science Center
  • Ida M. Green Award (1999) - Cecil and Ida Green Foundation

Grants and Contracts

Current Grant Funding

  • NHLBI R01-HL102758, ‘Daily Regulation of Ionic Currents’
  • NIMH R01-MH111527, ‘Multiparametric Biosensor Imaging in Brain Slice’
  • NHLBI/NINDS R13-HL134301, ‘Genetic and Animal Models for Ion Channel Function in Physiology and Disease’
  • S&R Foundation, The Ryuji Ueno Award for Ion Channels or Barrier Function Research

 

Completed

  • NIDDK R21 DK089337, ‘Intrinsic Circadian Rhythms in Bladder’
  • American Heart Association, National Center 0930232N, ‘Regulation of heart rate by BK potassium channels’
  • National Science Foundation IOS 0956237, ‘Circadian Patterning of Neuronal Activity and Behavior’

 

Mentored Grants

  • Breanne Wright - “The Effect of Transgenic Manipulation of the BK Channel (Kcnma1) on Circadian Rhythmicity”, The American Physiological Society Summer Undergraduate Fellowship
  • Zulqarnain Khan - “The Effect of GsMTx4 on Kcnma1–/– urinary bladder smooth muscle contractility, a mouse model of overactive bladder”, American Physiological Society Summer Undergraduate Fellowship
  • Zulqarnain Khan - “Using a smooth muscle deletion of BK channel (SM22-Cre; Kcnma1fl/fl) to evaluate its role in blood pressure regulation”, UMB PRISM Summer Medical Student Fellowship

 

In the News

Andrea Meredith’s lab and research efforts to help patients with KCNMA1-Linked Channelopathy in Netflix’s ‘Diagnosis’ documentary

Interviewed and provided expert opinion quote for “Ask Well” column (‘Can You Train Yourself to Need Less Sleep?’), The New York Times, June 17, 2016.

New study illuminates key aspects of how we fall asleep and wake up
Discovery could eventually lead to new and better treatments for insomnia and jet lag

Controlling our circadian rhythms

Support the KCNMA1 Channelopathy Research Program

Professional Activity

  • KCNMA1 Channelopathy International Advocacy Foundation
    — Co-Founder, Vice-President/Secretary
    — Basic Science Advisor and Patient Advocate (Volunteer)

  • Regular Member, Neurotransporters, Receptors, Channels and Calcium Signaling (NTRC) Study Section
  • Editorial Advisory Board, Journal of General Physiology
  • Councilor, Society of General Physiologists
  • Member, Neurotransporters, Receptors, Channels and Calcium Signaling (NTRC) Study Section, Center for Scientific Review, at the National Institutes of Health (NIH). 
  • Advisory board, Biophysical Society/Institute of Physics to create an ebook publications series on biophysics for the Biophysical Society (term 2017-2019)

Lab Techniques and Equipment

  • Molecular biology: generation of transgenic mice, RT-PCR, cloning, site-directed mutagenesis, transcript and protein expression, immunohistochemistry and in situ hybridization, microarray analysis of gene expression.
  • Electrophysiology: macroscopic currents, action potentials, single and multi-unit extracellular recordings, planar multi-electrode arrays, whole-cell recording, patch-clamp, acute brain slices, dissociated primary neuronal cultures, and organotypic cultures.
  • Systems physiology: telemetry (ECG, EEG, pressure, temperature), bladder cystometry, isometric tension recordings from smooth muscle, cardiovascular function, and circadian behavioral rhythms.

Links of Interest

Licensed Inventions

Docket #S02-267, Slo1 (Kcnma1–/–) Conditional Knockout Mice
Stanford University School of Medicine Office of Technology Licensing

Docket #AM2012-034, Tg-BKR207Q Transgenic mice
Docket #AM2013-078, Kcnma1fl-tdTomato Conditional Knockout Mice
UMB Office of Technology Transfer

Laboratory Personnel

  • Jenna Montgomery Harvey: Research Associate
  • Hans Moldenhauer: Postdoctoral Fellow
  • Su Mi Park: Postdoctoral Fellow
  • Amber Plante: Graduate Student
  • Cole Bailey: Medical Student