Studied the function and physiological role of BK potassium ion channels in the lab of Dr. Richard Aldrich, a member of the National Academy of Sciences.
Ph.D. in Neuroscience, The
Studied neuronal specification and differentiation, focusing on Mash1, a neural-specific basic helix-loop-helix transcription factor in the lab of Dr. Jane Johnson.
Awards and Funding
2008 Maryland Outstanding Young Scientist of the Year (presented by the Maryland Science Center).
The lab is supported by grants from the National Heart, Lung, and Blood Institute (NHLBI), the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), the National Science Foundation (NSF), the American Heart Association (AHA), and the S&R Foundation Ryuji Ueno Award for Ion Channels or Barrier Function Research (The American Physiological Society).
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 Big 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-/-; http://www.ibridgenetwork.org/stanford/mslo1-conditional-knockout-mouse).
Identifying novel roles for BK channels
BK channels are highly expressed in subsets of central neurons and smooth muscle, where they play prominent roles in shaping excitability. Less is known about BK channels 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 systems levels. This lack of redundancy has enabled us to use the BK channel deletion mouse as a selective 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. We recently identified a novel role for the BK channel in SCN circadian pacemaker function. Kcnma1-/- mice have degraded circadian behavioral and physiological rhythms, and their SCN neurons exhibit aberrant daily action potential rhythms in the SCN circuit.
Lab Techniques and Equipment:
Molecular biology: generation of transgenic mice, cloning, site-directed mutagenesis, transcript and protein expression, immunohistochemistry and in situ hybridization, microarray analysis of gene expression.
Electrophysiology: 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 and isometric tension recordings, cardiovascular regulation, and circadian behavioral rhythms.
Caption: Meredith Lab Members, 2009 (from back left): Mike Lai, Breanne Wright, Benyam Kinde, Hyunjin Choi, Andrea Meredith, and Jenna Montgomery
Jenna Montgomery, PhD (University of Bristol, UK): Postdoc, multi-electrode array recordings from acute and organotypic SCNs, patch-clamp recordings of BK currents.
Rachael White, PhD (University of Pennsylvania): Postdoc, SCN electrophysiology and circadian rhythms.
Mike Lai: Graduate Student, UMCP Bioengineering Program, cardiovascular telemetry, patch-clamp recordings of BK currents.
Josh Whitt: Graduate Student, Program in Neuroscience, molecular biology analysis of BK channel expression and localization.
Breanne Wright: Undergraduate at UMBC, Meyerhoff and MARC Scholar, American Physiological Society Summer Fellow (2010), mouse breeding and genotyping, circadian behavioral rhythms.
Betsir Zemen: Undergraduate at UMBC, tissue culture and general lab duties.
Rotation students - Of course! (contact me for more information)
Postdoc - Must have experience with electrophysiology (see ad)
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, 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 Physiology 304(4):C299-C311. PMCID: PMC3566534
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 A, 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.
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).
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.
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