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.
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-/-).
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.
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.
Behavior and System physiology: phenotyping screens, telemetry (ECG, EEG, pressure, temperature), cardiovascular regulation, circadian rhythms, and sleep.
- Jenna Montgomery, PhD: Postdoc, multi-electrode array recordings from acute and organotypic SCNs, patch-clamp recordings of BK currents.
- Mike Lai: Graduate Student, UMCP Bioengineering Program, telemetric recordings of cardiovascular function, patch-clamp recordings of BK currents.
- Hyun Jin Choi, MS: Graduate Student, Program in Neuroscience, molecular biology analysis of BK channel expression and localization.
- Breanne Wright: Undergraduate at UMBC, Meyerhoff Scholar, mouse breeding and genotyping.
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 Jun 22. doi: 10.1038/nn.3744. [Epub ahead of print]
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
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.
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, 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).
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, A and Johnson, JE (2000). Negative autoregulation of MASH1 expression in CNS development. Developmental Biology 222: 336-346.
Horton, S, Meredith, A, 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, A, 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.
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