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KCNMA1 Knockout Mice


Stanford Reference:

02-267


Abstract


Dr. Andrea Meredith and Dr. Richard Aldrich have generated a viable mouse knockout of KCNMA1 (Kcnma1-/-). The KCNMA1 gene encodes the pore-forming subunit of the BK large conductance calcium-activated potassium channel (also called KCa1.1, mSLO1, and MaxiK). BK channels are prominent regulators of excitability in neurons, smooth muscle and neuroendocrine tissues. Loss of BK channel function disrupts many physiological processes and can cause cerebellar ataxia, tremor, urinary incontinence, disruption of circadian rhythms, bradycardia, hypertension, hyperaldosteronism, impaired neurovascular coupling, erectile dysfunction, impaired hearing, impaired glucose homeostasis, impaired neuro- and cardio-protection, and altered learning and memory. These mice provide an excellent model for drug development and investigations into the various physiological roles of BK channels.

Stage of Research
Homozygous KCNMA1 knockouts (Kcnma1-/-) from this mouse line exhibit multiple phenotypes, including: ataxia, tremor, degraded circadian rhythms, reduced breeding efficiency (males and females), reduced body weight, smooth muscle hyper-contractility (leading to urinary incontinence, erectile dysfunction, and reduced cerebral vasodilation), altered olivo-cochlear inhibition, reduced adrenergic-stimulated K+ secretion in the colon, an impaired DHA-mediated blood pressure decrease, reduced cardio-protection in ischemia models, altered salivary secretion, reduced cortical collecting duct flow-stimulated net K+ secretion in kidney, resistance to alcohol intoxication, and reduced sino-atrial node firing rate.



Applications


  • Drug development and design:
    • Generate new therapeutics for disease caused by BK channel dysfunction
    • Evaluate drug and antibody specificity for KCNMA1
    • Isoform-selective pharmacology
      • Study effects of KCNMA1 alternative splice variants in knockout tissue/cell background
  • Disease model for:
    • Myogenic and neurogenic urinary incontinence
    • Erectile dysfunction
    • Primary circadian rhythm dysfunction
  • Research- study mechanistic role for BK channel in:
    • Neural excitability
    • Neuro-protection
    • Cardio-protection
    • Cardiac excitability
    • Tremor
    • Ataxia
    • Seizure
    • Familial hypokalemic periodic paralysis
    • Stroke
    • Vascular hypertension
    • Neuroendocrine regulation
    • Uterine contraction
    • Asthma
    • Sjogren’s syndrome
    • Alcoholism
    • Diabetes
    • Learning and memory
    • Autism

Advantages


  • Two inbred backgrounds - the mice are available on both C57BL6/J and FVBN/J backgrounds
  • The mice have pleiotropic phenotypes making them a useful system to study multiple roles of the BK channel
  • Applicable model of human disease

Publications


  • Primary publication reporting the generation of the Kcnma1-/- mice:
  • Additional publications using the Kcnma1-/- mice:
    • Hormonal: Lovell PV, McCobb DP (2001). Pituitary control of BK potassium channel function and intrinsic firing properties of adrenal chromaffin cells. J. Neurosci. 21:3429-42.
    • Houamed KM, Sweet IR, Satin LS (2010). BK channels mediate a novel ionic mechanism that regulates glucose-dependent electrical activity and insulin section in mouse pancreatic beta cells J Physiol. 588(18):3511-23.
    • Vascular Hypertension: Brenner R1, Peréz GJ, Bonev AD, Eckman DM, Kosek JC, Wiler SW, Patterson AJ, Nelson MT, Aldrich RW (2000). Vasoregulation by the beta1 subunit of the calcium-activated potassium channel. Nature 407:870-6.
    • Neuroprotection: Gribkoff VK1, Starrett JE Jr, Dworetzky SI, Hewawasam P, Boissard CG, Cook DA, Frantz SW, Heman K, Hibbard JR, Huston K, Johnson G, Krishnan BS, Kinney GG, Lombardo LA, Meanwell NA, Molinoff PB, Myers RA, Moon SL, Ortiz A, Pajor L, Pieschl RL, Post-Munson DJ, Signor LJ, Srinivas N, Taber MT, Thalody G, Trojnacki JT, Wiener H, Yeleswaram K, Yeola SW (2001). Targeting acute ischemic stroke with a calcium-sensitive opener of maxi-K potassium channels. Nat. Med. 7:471-7.
    • Bronchial: Ise S1, Nishimura J, Hirano K, Hara N, Kanaide H (2003). Theophylline attenuates Ca2+ sensitivity and modulates BK channels in porcine tracheal smooth muscle. Br. J. Pharmacol. 140:939-47.
    • Uterine Contraction: Khan RN, Smith SK, Ashford ML (1998). Contribution of calcium-sensitive potassium channels to NS1619-induced relaxation in human pregnant myometrium. Hum. Reprod. 13:208-13.
    • Learning & Memory: Typlt M1, Mirkowski M, Azzopardi E, Ruettiger L, Ruth P, Schmid S (2013). Mice with deficient BK channel function show impaired prepulse inhibition and spatial learning, but normal working and spatial reference memory" PLoS One 8(11):e81270.
    • 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. PNAS 110(26):10836-41.
    • 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.
    • 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. Journal of Neurophysiology 109(6):1525-1534.
    • Montgomery, JM, Whitt, JP, Wright, BN, Lai, ML, and Meredith, AL (2013). Mis-expression of the BK K+ channel disrupts suprachiasmatic nucleus circuit rhythmicity and alters clock-controlled behavior. AJP- Cell Physiology 304(4):C299-C311.
    • Hoshi, T, Wissuwa, B, Tian, Y, Tajima, T, Xu, R, Bauerb, M, Heinemann, S, and Hou, S (2013). Omega-3 fatty acids lower blood pressure by directly activating large-conductance Ca2+-dependent K+ channels. PNAS 110 (12): 4816–4821.
    • Lynch, FM, Withers, SB, Yao, Z, Werner, ME, Edwards, G, Weston, AH, Heagerty, AM (2013). Perivascular adipose tissue-derived adiponectin activates BKCa channels to induce anticontractile responses. American Journal of Physiology - Heart and Circulatory Physiology 304: H786-H795
    • Dabertrand, F, Nelson, MT, and Brayden, JE (2012). Acidosis Dilates Brain Parenchymal Arterioles by Conversion of Calcium Waves to Sparks to Activate BK Channels. Circulation Research 110: 285-294.
    • O’Brien, AJ, Terala, D, Orie, NN, Davies, NA, Zolfaghari, P, Singer, M, and Clapp, LH (2011). BK large conductance Ca2+-activated K+ channel deficient mice are not resistant to hypotension and display reduced survival benefit following polymicrobial sepsis. Shock 35(5): 485–491.
    • Girouard H, Bonev AD, Hannah, RM, Meredith AL, Aldrich RW and Nelson MT (2010). Astrocytic endfoot Ca2+ and BK channels determine both arteriolar dilation and constriction. PNAS 107(8):3811-6.
    • 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.
    • Kent, J and Meredith, AL (2008). BK channels regulate spontaneous action potential rhythmicity in the suprachiasmatic nucleus. PLoS One 3(12):e3884.
    • 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.
    • Petkov, GV, Brown, SM, Bentcheva-Petkov, LM, Meredith, AL, Aldrich, RW, and Nelson, MT (2008). The large conductance Ca2+-activated K+ (BK) channel mediates the smooth muscle relaxation in response to b-adrenergic receptor stimulation in the urinary bladder: Evidence from BK channel a-subunit knockout mice. AJP- Renal Physiol. 295(4):F1149-57.
    • Werner ME, Meredith AL, Aldrich RW, and Nelson MT. (2008) Hyper-contractility and impaired sildenafil relaxations in the BKCa channel deletion model of erectile dysfunction. AJP- Renal Physiol. 295:F1149-57.
    • Nakamoto, T, Romanenko, VG, Takahashi, A, Begenisich, T, Melvin, JE (2008). Apical maxi-K (KCa1.1) channels mediate K+ secretion by the mouse submandibular exocrine gland. American Journal of Physiology - Cell Physiology 294: C810-C819.
    • Pyott SJ, Meredith AL, Fodor AA, Yamoah EN and Aldrich RW. (2007). Normal cochlear function in mice lacking the BK channel α, β1 or β4 subunits. Journal Biological Chemistry 282:3312-3324.
    • Werner, ME, Zvara, P, Meredith, AL, Aldrich RW, and Nelson, MT (2007). Frequency encoding of cholinergic- and purinergic-mediated signaling to mouse urinary bladder smooth muscle: Modulation by BK channels. Am J Physiol Regul Integr Comp Physiol. 292: R616-624.
    • Romanenko, VG, Nakamoto, T, Srivastava, A, Begenisich, T, and Melvin, JE (2007). Regulation of membrane potential and fluid secretion by Ca2+-activated K+ channels in mouse submandibular glands. Journal of Physiology, 581, 801-817.
    • Filosa JA, Bonev AD, Straub SV, Meredith AL, Wilkerson MK, Aldrich RW and Nelson MT. (2006). Local potassium signaling couples neuron al activity to vasodilation in the brain. Nature Neurosci. 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.
    • Misonou H, Menegola M, Buchwalder L, Park EW, Meredith A, 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.
    • Romanenko V, Nakamoto T, Srivastava A, Melvin JE, and Begenisich T (2006). Molecular Identification and Physiological Roles of Parotid Acinar Cell Maxi-K Channels. Journal of Biological Chemistry 281, 27964-27972.
    • Werner, ME, Zvara, P, Meredith, AL, Aldrich RW, and Nelson, MT (2005). Erectile dysfunction in mice lacking the large conductance calcium-activated potassium (BK) channel. J Physiol. 567(2):545-556.
    • Thorneloe, KS, Meredith, AL, Knorn, AM, Aldrich, RW and Nelson, MT (2005). Urodynamic properties and neurotransmitter dependence of urinary bladder contractility in the BK channel deletion model of overactive bladder. Am J Physiol Renal Physiol. 289(3):F604-10.

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Date Released

 6/26/2014
 

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ion channels   research tool: mouse model   circadian rhythm   erectile dysfunction   ion channel modulators   drug development   disease model   cardioprotection   genitourinary   urinary incontinence   mouse cage   neuroprotection   therapeutic: disease model   therapeutic: drug design   urinary bladder   urinary tract   
 

   

  

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