Description

Strain Information

Type Congenic; Mutant Strain; Targeted Mutation; Additional information on Genetically Engineered Mutant Mice. Species laboratory mouse   Donating Investigator Brian Kobilka,   Stanford University

Description
Mice that are homozygous for the targeted mutation are viable, normal in size and do not display any gross physical or behavioral abnormalities. Expression of the receptor in the brain was significantly reduced as assessed by antagonist binding, which indicated a 90% reduction. The antagonist binding assay is not entirely specific for the receptor, as the residual 10% binding was attributable to a different subtype of receptor. Mutant mice exhibit a resting tachycardia of more than 180 beats/min greater than normal. Although mutant mice do not have elevated blood pressure, administration of the hypotensive agonist, dexmedetomidine, does not reduce blood pressure. Electrical stimulation of isolated heart atria at frequencies mimicking physiological sympathetic nerve activity results in increased release of noradrenaline at high frequencies and inhibited release at low frequencies. Noradrenaline release from isolated wildtype atria is higher at high frequencies than at low frequencies. Inhibition of neurogenic contraction response to electrical stimulation in isolated vas deferens by dexmedetomidine is reduced in the mutant.

Development
A targeting vector containing neomycin resistance gene driven by the mouse phosphoglycerate kinase promoter and herpes simplex virus thymidine kinase gene was used to disrupt the sequence of the targeted gene encoding the third transmembrane domain. The construct was electroporated into 129X1/SvJ x 129S1/Sv derived R1 embryonic stem (ES) cells. Correctly targeted ES cells were aggregated with 8-cell FVB/N morulae. The resulting chimeric animals were backcrossed to C57BL/6 mice.

Related Strains

Strains carrying other alleles of Adra2a

002777

B6.129S2-Adra2atm1Lel/J

View Strains carrying other alleles of Adra2a     (1 strain)

Additional Web Information

Congenic Nomenclature

Phenotype

Phenotype Information

View Mammalian Phenotype Terms

Mammalian Phenotype Terms

      assigned by genotype

The following phenotype information may relate to a genetic background differing from this JAX^® Mice strain.

Adra2a^tm1Bkk/Adra2a^tm1Bkk

        involves: 129S1/Sv * 129X1/SvJ * C57BL/6

• cardiovascular system phenotype
• abnormal blood pressure (MGI Ref ID J:76317)
  • unlike wild-type controls, administration of the hypotensive agonist, dexmedetomidine, did not reduce blood pressure
• increased heart rate (MGI Ref ID J:76317)
  • resting heart rate more than 180 beats/min greater than normal
• nervous system phenotype
• abnormal synaptic norepinephrine release (MGI Ref ID J:58591)
  • increased release at high frequency electrical stimulation
  • decreased release at low frequency electrical stimulation

Adra2a^tm1Bkk/Adra2a^tm1Bkk

        involves: 129S1/Sv * 129X1/SvJ

• homeostasis/metabolism phenotype
• abnormal glucose homeostasis (MGI Ref ID J:130781)
  • unlike in wild-type mice, hyperglycemia cannot be induced by treatment with 3-iodothyronamine and/or 6-OH dopamine
• hypoglycemia (MGI Ref ID J:130781)
  • following treatment with 3-iodothyronamine

View Research Applications

Research Applications

This mouse can be used to support research in many areas including:

Adra2a^tm1Bkk related

Cardiovascular Research
Heart Abnormalities (tachycardia)
Hypotension

Neurobiology Research
Epilepsy

Genes & Alleles

Gene & Allele Information

Allele Symbol		Adra2atm1Bkk
Allele Name		targeted mutation 1, Brian K Kobilka
Allele Type		Targeted (knock-out)
Common Name(s)		alpha2A-; alpha2A-AR-; alpha2A-ARKO; alpha2A-KO;
Mutation Made By		Brian Kobilka,   Stanford University
Strain of Origin		(129X1/SvJ x 129S1/Sv)F1-Kitl<+>
ES Cell Line Name		R1
ES Cell Line Strain		(129X1/SvJ x 129S1/Sv)F1-Kitl<+>
Gene Symbol and Name		Adra2a, adrenergic receptor, alpha 2a
Chromosome		19
Gene Common Name(s)		ADRA2; ADRA2R; ADRAR; ALPHA2AAR; AW122659; Adra-2; Adra-2a; RATRG20; RG20; ZNF32; adrenergic receptor, alpha 2; alpha(2A)AR; alpha2-C10; alpha2A; alpha2A-AR; alpha2A-adrenergic receptor; expressed sequence AW122659; subtype alpha2-C10;
Molecular Note		A neomycin cassette inserted into the gene by homologous recombination resulted in a premature stop codon within the third transmembrane domain. Confirmation of the targeting event was demonstrated through Southern analysis. [MGI Ref ID J:76317]

Genotyping

Genotyping Information

Genotyping Protocols

Adra2a^tm1Bkk, STD PCR, vers. 1

Helpful Links

Optimizing PCR Protocols

References

References

Selected Reference(s)

Altman JD; Trendelenburg AU; MacMillan L; Bernstein D; Limbird L; Starke K; Kobilka BK; Hein L. 1999. Abnormal regulation of the sympathetic nervous system in alpha2A-adrenergic receptor knockout mice. Mol Pharmacol 56(1):154-61. [PubMed: 10385696]  [MGI Ref ID J:76317]

Additional References

Hein L; Altman JD; Kobilka BK. 1999. Two functionally distinct alpha2-adrenergic receptors regulate sympathetic neurotransmission. Nature 402(6758):181-4. [PubMed: 10647009]  [MGI Ref ID J:58591]

Adra2a^tm1Bkk related

Bonaventure P; Nepomuceno D; Hein L; Sutcliffe JG; Lovenberg T; Hedlund PB. 2004. Radioligand binding analysis of knockout mice reveals 5-hydroxytryptamine(7) receptor distribution and uncovers 8-hydroxy-2-(di-n-propylamino)tetralin interaction with alpha(2) adrenergic receptors. Neuroscience 124(4):901-11. [PubMed: 15026130]  [MGI Ref ID J:89990]

Brede M; Nagy G; Philipp M; Sorensen JB; Lohse MJ; Hein L. 2003. Differential control of adrenal and sympathetic catecholamine release by alpha 2-adrenoceptor subtypes. Mol Endocrinol 17(8):1640-6. [PubMed: 12764077]  [MGI Ref ID J:126731]

Brum PC; Kosek J; Patterson A; Bernstein D; Kobilka B. 2002. Abnormal cardiac function associated with sympathetic nervous system hyperactivity in mice. Am J Physiol Heart Circ Physiol 283(5):H1838-45. [PubMed: 12384461]  [MGI Ref ID J:108048]

Bucheler MM; Hadamek K; Hein L. 2002. Two alpha(2)-adrenergic receptor subtypes, alpha(2A) and alpha(2C), inhibit transmitter release in the brain of gene-targeted mice. Neuroscience 109(4):819-26. [PubMed: 11927164]  [MGI Ref ID J:126644]

Davies MF; Tsui JY; Flannery JA; Li X; DeLorey TM; Hoffman BB. 2003. Augmentation of the noradrenergic system in alpha-2 adrenergic receptor deficient mice: anatomical changes associated with enhanced fear memory. Brain Res 986(1-2):157-65. [PubMed: 12965240]  [MGI Ref ID J:107779]

Fagerholm V; Gronroos T; Marjamaki P; Viljanen T; Scheinin M; Haaparanta M. 2004. Altered glucose homeostasis in alpha2A-adrenoceptor knockout mice. Eur J Pharmacol 505(1-3):243-52. [PubMed: 15556159]  [MGI Ref ID J:101927]

Ferreira JC; Bacurau AV; Evangelista FS; Coelho MA; Oliveira EM; Casarini DE; Krieger JE; Brum PC. 2008. The role of local and systemic renin angiotensin system activation in a genetic model of sympathetic hyperactivity-induced heart failure in mice. Am J Physiol Regul Integr Comp Physiol 294(1):R26-32. [PubMed: 17977919]  [MGI Ref ID J:130320]

Hein L; Altman JD; Kobilka BK. 1999. Two functionally distinct alpha2-adrenergic receptors regulate sympathetic neurotransmission. Nature 402(6758):181-4. [PubMed: 10647009]  [MGI Ref ID J:58591]

Ihalainen JA; Tanila H. 2004. In vivo regulation of dopamine and noradrenaline release by alpha2A-adrenoceptors in the mouse nucleus accumbens. J Neurochem 91(1):49-56. [PubMed: 15379886]  [MGI Ref ID J:93277]

Ihalainen JA; Tanila H. 2002. In vivo regulation of dopamine and noradrenaline release by alpha2A-adrenoceptors in the mouse prefrontal cortex. Eur J Neurosci 15(11):1789-94. [PubMed: 12081658]  [MGI Ref ID J:108075]

Juhila J; Honkanen A; Sallinen J; Haapalinna A; Korpi ER; Scheinin M. 2005. alpha(2A)-Adrenoceptors regulate d-amphetamine-induced hyperactivity and behavioural sensitization in mice. Eur J Pharmacol 517(1-2):74-83. [PubMed: 15978573]  [MGI Ref ID J:103792]

Knaus A; Zong X; Beetz N; Jahns R; Lohse MJ; Biel M; Hein L. 2007. Direct inhibition of cardiac hyperpolarization-activated cyclic nucleotide-gated pacemaker channels by clonidine. Circulation 115(7):872-80. [PubMed: 17261653]  [MGI Ref ID J:132333]

Lahdesmaki J; Sallinen J; MacDonald E; Kobilka BK; Fagerholm V; Scheinin M. 2002. Behavioral and neurochemical characterization of alpha(2A)-adrenergic receptor knockout mice. Neuroscience 113(2):289-99. [PubMed: 12127086]  [MGI Ref ID J:109288]

Lahdesmaki J; Sallinen J; MacDonald E; Sirvio J; Scheinin M. 2003. Alpha2-adrenergic drug effects on brain monoamines, locomotion, and body temperature are largely abolished in mice lacking the alpha2A-adrenoceptor subtype. Neuropharmacology 44(7):882-92. [PubMed: 12726820]  [MGI Ref ID J:97152]

Lahdesmaki J; Scheinin M; Pertovaara A; Mansikka H. 2003. The alpha2A-adrenoceptor subtype is not involved in inflammatory hyperalgesia or morphine-induced antinociception. Eur J Pharmacol 468(3):183-9. [PubMed: 12754056]  [MGI Ref ID J:102597]

Makaritsis KP; Johns C; Gavras I; Altman JD; Handy DE; Bresnahan MR; Gavras H. 1999. Sympathoinhibitory function of the alpha(2A)-adrenergic receptor subtype. Hypertension 34(3):403-7. [PubMed: 10489385]  [MGI Ref ID J:59489]

Mansikka H; Lahdesmaki J; Scheinin M; Pertovaara A. 2004. Alpha(2A) adrenoceptors contribute to feedback inhibition of capsaicin-induced hyperalgesia. Anesthesiology 101(1):185-90. [PubMed: 15220790]  [MGI Ref ID J:105328]

Moura E; Afonso J; Hein L; Vieira-Coelho MA. 2006. Alpha2-adrenoceptor subtypes involved in the regulation of catecholamine release from the adrenal medulla of mice. Br J Pharmacol 149(8):1049-58. [PubMed: 17075569]  [MGI Ref ID J:135922]

Niederhoffer N; Hein L; Starke K. 2004. Modulation of the baroreceptor reflex by alpha 2A-adrenoceptors: a study in alpha 2A knockout mice. Br J Pharmacol 141(5):851-9. [PubMed: 14769782]  [MGI Ref ID J:102353]

Ozdogan UK; Lahdesmaki J; Hakala K; Scheinin M. 2004. The involvement of alpha 2A-adrenoceptors in morphine analgesia, tolerance and withdrawal in mice. Eur J Pharmacol 497(2):161-71. [PubMed: 15306201]  [MGI Ref ID J:101972]

Ozdogan UK; Lahdesmaki J; Mansikka H; Scheinin M. 2004. Loss of amitriptyline analgesia in alpha 2A-adrenoceptor deficient mice. Eur J Pharmacol 485(1-3):193-6. [PubMed: 14757140]  [MGI Ref ID J:103497]

Ozdogan UK; Lahdesmaki J; Scheinin M. 2006. The analgesic efficacy of partial opioid agonists is increased in mice with targeted inactivation of the alpha2A-adrenoceptor gene. Eur J Pharmacol 529(1-3):105-13. [PubMed: 16325800]  [MGI Ref ID J:106379]

Paris A; Mantz J; Tonner PH; Hein L; Brede M; Gressens P. 2006. The effects of dexmedetomidine on perinatal excitotoxic brain injury are mediated by the alpha2A-adrenoceptor subtype. Anesth Analg 102(2):456-61. [PubMed: 16428542]  [MGI Ref ID J:134285]

Paris A; Philipp M; Tonner PH; Steinfath M; Lohse M; Scholz J; Hein L. 2003. Activation of alpha 2B-adrenoceptors mediates the cardiovascular effects of etomidate. Anesthesiology 99(4):889-95. [PubMed: 14508322]  [MGI Ref ID J:106006]

Philipp M; Brede ME; Hadamek K; Gessler M; Lohse MJ; Hein L. 2002. Placental alpha(2)-adrenoceptors control vascular development at the interface between mother and embryo. Nat Genet 31(3):311-5. [PubMed: 12068299]  [MGI Ref ID J:77486]

Pozgajova M; Sachs UJ; Hein L; Nieswandt B. 2006. Reduced thrombus stability in mice lacking the alpha2A-adrenergic receptor. Blood 108(2):510-4. [PubMed: 16507775]  [MGI Ref ID J:135683]

Regard JB; Kataoka H; Cano DA; Camerer E; Yin L; Zheng YW; Scanlan TS; Hebrok M; Coughlin SR. 2007. Probing cell type-specific functions of Gi in vivo identifies GPCR regulators of insulin secretion. J Clin Invest 117(12):4034-43. [PubMed: 17992256]  [MGI Ref ID J:130781]

Rolim NP; Medeiros A; Rosa KT; Mattos KC; Irigoyen MC; Krieger EM; Krieger JE; Negrao CE; Brum PC. 2007. Exercise training improves the net balance of cardiac Ca2+ handling protein expression in heart failure. Physiol Genomics 29(3):246-52. [PubMed: 17244791]  [MGI Ref ID J:128677]

Sawamura S; Kingery WS; Davies MF; Agashe GS; Clark JD; Kobilka BK; Hashimoto T; Maze M. 2000. Antinociceptive action of nitrous oxide is mediated by stimulation of noradrenergic neurons in the brainstem and activation of [alpha]2B adrenoceptors. J Neurosci 20(24):9242-51. [PubMed: 11125002]  [MGI Ref ID J:120560]

Scheibner J; Trendelenburg AU; Hein L; Starke K. 2001. Alpha2-adrenoceptors modulating neuronal serotonin release: a study in alpha2-adrenoceptor subtype-deficient mice. Br J Pharmacol 132(4):925-33. [PubMed: 11181434]  [MGI Ref ID J:115396]

Scheibner J; Trendelenburg AU; Hein L; Starke K; Blandizzi C. 2002. Alpha 2-adrenoceptors in the enteric nervous system: a study in alpha 2A-adrenoceptor-deficient mice. Br J Pharmacol 135(3):697-704. [PubMed: 11834617]  [MGI Ref ID J:103275]

Tan CM; Wilson MH; MacMillan LB; Kobilka BK; Limbird LE. 2002. Heterozygous alpha 2A-adrenergic receptor mice unveil unique therapeutic benefits of partial agonists. Proc Natl Acad Sci U S A 99(19):12471-6. [PubMed: 12205290]  [MGI Ref ID J:127138]

Trendelenburg AU; Hein L; Gaiser EG; Starke K. 1999. Occurrence, pharmacology and function of presynaptic alpha2-autoreceptors in alpha2A/D-adrenoceptor-deficient mice Naunyn Schmiedebergs Arch Pharmacol 360(5):540-51. [PubMed: 10598793]  [MGI Ref ID J:59811]

Health & husbandry

Health & Colony Maintenance Information

Colony Maintenance

Breeding & Husbandry	This strain originated on a FVB;129 background, has been backcrossed for 5 generations to C57BL/6 and may be maintained as a homozygote. Donating Investigator reports mutant mice usually have less than 6 litters and less than 6 pups per litter.

Purchasing information

Pricing, Supply Level & Notes, Controls, General Terms & Conditions

Pricing

Supply Details

Standard Supply

Repository-Cryopreserved. Must Be Recovered. Please refer to pricing and supply notes for further information.

Supply Notes

Cryopreserved Embryos This strain is also available as cryopreserved embryos from our Repository. Orders for cryopreserved embryos are supplied subject to a signed agreement that must be returned to the Customer Service Department after order placement. Experienced technicians at The Jackson Laboratory have recovered frozen embryos of this strain successfully. We will provide you enough embryos to perform two embryo transfers. The Jackson Laboratory does not guarantee successful recovery at your facility. For complete information on purchasing embryos from our repository, please visit our Cryopreserved Embryos web page. Cryorecovery - Standard. The recovery process begins when a signed agreement form is returned to the Customer Service Department after order placement. Although results vary by strain, at least two males and two females (two pairs) will be provided, typically within 15 weeks of our receipt of the signed agreement form. If the first recovery attempt is unsuccessful or only one pair is recovered, a second recovery will be done, extending the delivery time to approximately 25 weeks. At least one member of each pair will be of known genotype and will carry the mutation if it is a mutant strain. Please note that pairs may not reflect the mating scheme utilized by The Jackson Laboratory prior to cryopreservation of the strain. Mating schemes are sometimes modified for successful cryopreservation. Price represents a repository maintenance fee, which includes the cost of recovery of the strain from the cryopreservation resource and the periodic replacement of the frozen embryos used for recovery. Cryorecovery to establish a Dedicated Supply for greater quantities of mice. One to two pairs will be recovered to establish a Dedicated Supply of mice. Price by quotation. For more information on Dedicated Supply, please contact JAX® Services, Tel: 1-800-422-6423 or 1-207-288-5845. This strain is included in the Induced Mutant Resource Colony collection.

General Terms and Conditions

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The Jackson Laboratory's Genotype Promise

The Jackson Laboratory has rigorous genetic quality control and mutant gene genotyping programs to ensure the genetic background of JAX^® Mice strains as well as the genotypes of strains with identified molecular mutations. JAX^® Mice strains are only made available to researchers after meeting our standards. However, the phenotype of each strain may not be fully characterized and/or captured in the strain data sheets. Therefore, we cannot guarantee a strain's phenotype will meet all expectations. To ensure that JAX^® Mice will meet the needs of individual research projects or when requesting a strain that is new to your research, we suggest ordering and performing tests on a small number of mice to determine suitability for your particular project.

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Terms of Use

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General Terms and Conditions

For Licensing and Use Restrictions view the link(s) below:
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phone:	207-288-6470
fax:	207-288-6655

JAX^® Mice & Services Conditions of Use

“Each recipient institution, including its employees and other researchers under its control (RECIPIENT), of mice or services using mice from The Jackson Laboratory (TJL) agrees that such mice, descendants of those mice derived by inbreeding or crossbreeding, including unmodified derivatives of those mice or their descendants (“MICE”) shall not be: (i) used for any purpose other than the internal research of the RECIPIENT, (ii) sold or otherwise provided to any third party for any use, or (iii) provided to any agent or other third party to provide breeding or other services with respect to MICE. Acceptance of MICE from TJL shall be deemed agreement by RECIPIENT to these conditions, and departure from these conditions requires The Jackson Laboratory’s prior written authorization.”

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