Andrea L. Meredith, PhD

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.

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

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 States. PLoS 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+ stores. Journal 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 system. Neuron 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 hypertension. European 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 mitoBK_Ca 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 channels. J 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 neurons. J 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 development. Developmental 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 MASH1. Molecular 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.

My research focus is the biophysical and membrane basis for information coding. For the past 22 years, I have focused on a unique ion channel, Big K⁺ (BK), the large conductance voltage- and Ca²⁺-activated K⁺ channel widely expressed neurons, muscle, and non-excitable cells. In my lab, we use a multi-disciplinary approach to uncover the physiological roles of the BK channel using approaches in membrane biophysics, neurophysiology, and transgenics.  Our studies correlate information from the membrane/channel, cellular, circuit, and animal levels, providing a translational understanding of how ion channels, like BK, regulate neurophysiology and disease.

In the lab, we use patch-clamp electrophysiology and the analysis of ionic current properties from channels expressed in heterologous cells, neurons, and muscle.  Our recording techniques also include: current-clamp recordings and action potential waveform analysis, multi-electrode array recordings and ensemble circuit analysis, quantitative in vivo physiology in awake, behaving mice (telemetric recordings of brain EEG, cardiac ECG, blood pressure, core body temperature, and locomotor activity), and circadian and neurological behavioral analysis.  We generate transgenic mice and cell lines (Kcnma1^–/–, Tg-BK^R207Q, Kcnma1^flox-tdTomato, Kcnma1^D434G, Kcnma1^N999S, and Kcnma1^H444Q), encompassing both loss- and gain-of-function alterations in BK channel activity, and clone/quantify KCNMA1 splice variants and accessory subunits that underlie BK current properties in native tissues.  

KCNMA1-Linked Channelopathy

My lab has played a central role in characterizing a new seizure and dyskinesia disorder, ‘KCNMA1-Linked channelopathy’.  As part of this effort, we mobilized our research pipeline to assist patients identified with novel KCNMA1 variants affecting the pore-forming subunit of the BK channel.  Starting with a little girl with severe dyskinesia and seizures who was featured in the NYTimes medical mystery column, ‘Diagnosis,’ about 120 patients have been identified with KCNMA1 mutations. No BK channel-selective treatments currently exist, so we partnered directly with patients to study how their novel mutations alter BK channel activity.  We discovered that a class of gain-of-function (GOF) mutations that produce aberrant and massive increases in BK channel gating, providing a basis to make a novel drug recommendation for the intractable symptoms experienced by the child.  We are currently studying many KCNMA1 patient mutations associated with a range of neurological symptoms.  These mutations alter BK channel activity through distinct loss- and gain-of function mechanisms, which we are investigating in biophysical, animal, and human studies.  Find out more about this  very rare KCNMA1-linked channelopathy here.

The Biophysical Basis for Circadian Rhythm 

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. 

I demonstrated that a daily oscillation in BK channel expression provides the critical link between the ‘clock genes’ that encode time in individual SCN neurons and physiological/behavioral rhythmicity, summarized in a News and Views article (Nat Neuro 9:985-996, 2006).  Kcnma1^–/– mice have degraded behavioral rhythms, and we showed that this stemmed from loss of circadian patterning of neuronal activity in the SCN circuit.  While these knockout studies revealed the necessity of the BK channel for circadian rhythmicity, we went a step further and generated a gain-of-function transgenic line (Tg-BK^R207Q) to demonstrate the requirement for proper phasing of the BK current in SCN neurons.  Aberrant elevation of the BK current during the day in the SCN of Tg-BK^R207Q mice forces the circuit into a ‘down-state,’ decreasing rhythmicity and leading to behavioral alterations.  This study provided the first evidence that circadian modulation of an ionic current is critical for circuit rhythmicity, offering a novel entry point for the treatment of sleep and other disorders of circadian rhythmicity. 

Our most recent work has focused on understanding the fundamental molecular and biophysical mechanisms for rhythmic regulation of BK currents in the SCN.  We identified diurnal modulation of BK channel expression levels, alternative splicing, calcium regulation, and beta subunit mediated inactivation as the critical integrated mechanisms underlying BK’s dynamic role in the circadian patterning of neural activity.  By separately determining how these mechanisms alter BK channel activity in both heterologous cells and native SCN neurons, we were able to pinpoint beta2-mediated channel inactivation as the principal mechanism required for BK’s control of rhythmicity.  We showed that loss of inactivation altered the diurnal modulation of BK current, action potential, circuit, and circadian behavioral rhythms, and that selective restoration of inactivation via a ball-and-chain mechanism could restore these deficits.  This study showed that diurnal modulation of a biophysical ion channel gating property was central to encoding membrane rhythmicity and circadian time. 

• 2022 UMSOM Faculty Mentor Award for Transformational Impact, 45th Annual Medical Student Research Day
• 2021 Biophysical Society Award in the Biophysics of Health and Disease, for work on the new neuromuscular disorder, KCNMA1 Channelopathy.  This award honors a Biophysical Society member who has made a significant contribution to understanding the fundamental cause or pathogenesis of disease, enabling the treatment or prevention. The award will be presented at the upcoming 2021 annual meeting of the Biophysical Society.  Biophysical Society Bulletin October 2020 
• 2018 Molecular Devices Women in Science award, 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 and Allan C. Davis Medal (2008) - The Maryland Science Center
• Ida M. Green Award (1999) - Cecil and Ida Green Foundation

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

• Indira Jetton - ‘Precision medicine in KCNMA1 Channelopathy and NIH Undiagnosed Diseases (UDN) Program Clinical Trial Collaboration,’ KCNMA1 International Advocacy Foundation (KCIAF) Summer Medical Fellowship
• Jacob Miller - ‘Defining the Phenotypic Spectrum for KCNMA1-linked Channelopathy’,’ UMB PRISM Summer Medical Student Fellowship
• Cole Bailey - ‘Defining New KCNMA1 Channelopathies,’ UMB PRISM Summer Medical Student Fellowship
• 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

‘Collectively Intelligent,’ a profile on jour KCNMA1 studies in Creating Chemistry (BASF), Issue 12, 2023.

Gene Screen - A serendipitous crowdsourcing project changed the trajectory of Andrea Meredith’s research, connecting her directly with patients of a mysterious disease.  Featured article from the January 2020 issue of The Physiologist Magazine.  Interview by Melanie Padgett Powers.

Maryland professor Andrea Meredith on BK channelopathies, her KCNMA1 foundation and patching on sewing machines.  Featured article in iochannellibrary on June 9, 2020.  Interview by Artem Kondratskyi.

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

Humans of Neuroscience profile (December 22, 2022)

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

KCNMA1 Channelopathy International Advocacy Foundation 

• Co-Founder, Vice-President, and Secretary
• Basic Science Advisor and Patient Advocate 

• Editorial Advisory Board, Journal of General Physiology
• Editorial advisory board, Biophysical Society/Institute of Physics ebook publications series on biophysics (2017-2020)
• Standing Member, Neurotransporters, Receptors, Channels and Calcium Signaling (NTRC) Study Section (2016-2020)
• Councilor, Society of General Physiologists (2013-2019)
• Advisory board, Biophysical Society/Institute of Physics to create an ebook publications series on biophysics for the Biophysical Society (term 2017-2019)

• 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.

KCNMA1 Channelopathy International Advocacy Foundation 

Meredith Lab Website

Society of General Physiologists  

Biophysical Society

Donation link for the KCNMA1 Channelopathy Research Program

UMB Office of Technology Transfer

• Docket #AM2012-034, Tg-BKR207Q Transgenic mice
• Docket #AM2013-078, Kcnma1fl-tdTomato Conditional Knockout Mice
• Docket #AM-2019-104 (Kcnma1-D434G), 105 (Kcnma1-H444Q), 106 (Kcnma1-R1097H), and AM-2021-018 (Kcnma1-N999S), CRISPR-generated patient knock-in transgenic mouse lines 

Stanford University School of Medicine Office of Technology Licensing

• Docket #S02-267, Slo1 (Kcnma1–/–) Conditional Knockout Mice

• Hans Moldenhauer: Research Associate
• Ria Dinsdale: Postdoctoral Fellow
• Su Mi Park: Postdoctoral Fellow
• Cooper Roache: Graduate Student
• Jacob Miller: Medical Student 
• Kelly Tammen:  Undergraduate Student
• Marie-Rose Mayifuila:  Technician Assistant