* 104220

ALPHA-1B-ADRENERGIC RECEPTOR; ADRA1B


Alternative titles; symbols

ALPHA-1-ADRENERGIC RECEPTOR; ADRA1


HGNC Approved Gene Symbol: ADRA1B

Cytogenetic location: 5q33.3     Genomic coordinates (GRCh38): 5:159,865,086-159,989,205 (from NCBI)


TEXT

Description

Adrenergic receptors belong to the superfamily of G protein-coupled 7-transmembrane domain receptors. In response to external catecholamine stimuli, these receptors mediate a variety of cellular processes such as cardiac and atrial smooth muscle contraction (summary by Ramarao et al., 1992).


Cloning and Expression

Using the hamster Adra1b sequence to screen a heart cDNA library, Ramarao et al. (1992) cloned the human alpha-1B-adrenergic receptor. The deduced protein contains 517 amino acids and has a molecular mass of 56.7 kD. The human and mouse protein sequences share 98% homology. Northern blot analysis identified 2.8-kb ADRA1B transcripts predominantly in heart but also in kidney and brain.


Gene Structure

Ramarao et al. (1992) found that the ADRA1B gene comprises 2 exons and a single large intron of at least 20 kb that interrupts the coding region at the end of the putative sixth transmembrane domain. The genomic organization of this adrenergic receptor with a single large intron interrupting its coding region differs from those of previously described adrenergic receptors as well as muscarinic and 5-hydroxytryptamine receptors, which are intronless. The location of the intron is also unique among those members of the G protein-coupled receptor family that do possess introns.


Mapping

Yang-Feng et al. (1990) mapped the ADRA1 gene to chromosome 5 by Southern analysis of somatic cell hybrids and regionalized it to 5q32-q34 by in situ hybridization. From pulsed field gel electrophoresis, they concluded that the ADRA1R and ADRB2R (109690) loci are within 300 kb of each other. Lomasney et al. (1991) indicated that this alpha-1 receptor is alpha-1B and that the regional assignment is 5q23-q32. The corresponding gene in the mouse, symbolized Adra1r, is located on proximal chromosome 11 (Oakey et al., 1991).

Loftus et al. (1994) concluded that ADRA1B and ADRB2 are several Mb apart rather than a few hundred kb as reported by Yang-Feng et al. (1990).


Gene Function

When transfected into NIH 3T3 fibroblasts and other cell lines, the alpha-1B-adrenergic receptor induces neoplastic transformation which identifies this normal cellular gene as a protooncogene. Allen et al. (1991) demonstrated that mutational alteration of the receptor can lead to activation of this protooncogene in such a way that cell lines are constitutively activated, even though not stimulated by agonist. These cells demonstrate an enhanced ability for tumor generation in nude mice, with a decreased period of latency compared with cells expressing the wildtype receptor. From these observations, Allen et al. (1991) suggested that analogous spontaneously occurring mutations in this class of receptor proteins could play a key role in the induction or progression of neoplastic transformation and atherosclerosis. Indeed, a comparable situation was demonstrated in the case of the thyrotropin receptor, causing hyperfunctioning thyroid adenoma (275200.0002). Furthermore, a mutation in the luteinizing hormone receptor can result in its constitutive activation, resulting in familial male precocious puberty (152790.0001).


Molecular Genetics

The distal end of 5q, 5q31.1-qter, contains the genes for 2 adrenergic receptors, ADRB2 (109690) and ADRA1B, and the dopamine receptor type 1A gene (DRD1A; 126449). Krushkal et al. (1998) used an efficient discordant sib-pair ascertainment scheme to investigate the impact of this region of the genome on variation in systolic blood pressure in young Caucasians. They measured 8 highly polymorphic markers spanning this positional candidate gene-rich region in 427 individuals from 55 3-generation pedigrees containing 69 discordant sib pairs, and calculated multipoint identity by descent probabilities. The results of genetic linkage and association tests indicated that the region between markers D5S2093 and D5S462 was significantly linked to 1 or more polymorphic genes influencing interindividual variation in systolic blood pressure levels. Since the ADRA1B and DRD1A genes are located close to these markers, the data suggested that genetic variation in 1 or both of these G protein-coupled receptors, which participate in the control of vascular tone, plays an important role in influencing interindividual variation in systolic blood pressure levels.


Animal Model

Cavalli et al. (1997) used a gene targeting approach to create a mouse model lacking the alpha-1b-AR. Total alpha-1-AR sites were decreased by 98% in liver, 74% in heart, and 42% in cerebral cortex in alpha-lb-AR -/- mice as compared with +/+ mice. Because of the large decrease of alpha-1-AR in the heart and the loss of the ADRA1B mRNA in the aorta of the -/- mice, the in vivo blood pressure and in vitro aorta contractile responses to alpha-1-agonists were investigated in +/+ and -/- mice. The findings provided strong evidence that this receptor is a mediator of the blood pressure and aorta contractile responses induced by alpha-1 agonists. This was demonstrated by the finding that the mean arterial pressure response to phenylephrine was decreased by 45% in -/- mice as compared with +/+ mice. In addition, phenylephrine-induced contractions of aortic rings also were decreased by 25% in -/- mice.


REFERENCES

  1. Allen, L. F., Lefkowitz, R. J., Caron, M. G., Cotecchia, S. G-protein-coupled receptor genes as protooncogenes: constitutively activating mutation of the alpha-1B-adrenergic receptor enhances mitogenesis and tumorigenicity. Proc. Nat. Acad. Sci. 88: 11354-11358, 1991. [PubMed: 1662393, related citations] [Full Text]

  2. Cavalli, A., Lattion, A.-L., Hummler, E., Nenniger, M., Pedrazzini, T., Aubert, J.-F., Michel, M. C., Yang, M., Lembo, G., Vecchione, C., Mostardini, M., Schmidt, A., Beermann, F., Cotecchia, S. Decreased blood pressure response in mice deficient of the alpha(1b)-adrenergic receptor. Proc. Nat. Acad. Sci. 94: 11589-11594, 1997. [PubMed: 9326654, images, related citations] [Full Text]

  3. Krushkal, J., Xiong, M., Ferrell, R., Sing, C. F., Turner, S. T., Boerwinkle, E. Linkage and association of adrenergic and dopamine receptor genes in the distal portion of the long arm of chromosome 5 with systolic blood pressure variation. Hum. Molec. Genet. 7: 1379-1383, 1998. [PubMed: 9700190, related citations] [Full Text]

  4. Loftus, S. K., Shiang, R., Warrington, J. A., Bengtsson, U., McPherson, J. D., Wasmuth, J. J. Genes encoding adrenergic receptors are not clustered on the long arm of human chromosome 5. Cytogenet. Cell Genet. 67: 69-74, 1994. [PubMed: 8039425, related citations] [Full Text]

  5. Lomasney, J. W., Cotecchia, S., Lorenz, W., Leung, W.-Y., Schwinn, D. A., Yang-Feng, T. L., Brownstein, M., Lefkowitz, R. J., Caron, M. G. Molecular cloning and expression of the cDNA for the alpha-1A-adrenergic receptor: the gene for which is located on human chromosome 5. J. Biol. Chem. 266: 6365-6369, 1991. [PubMed: 1706716, related citations]

  6. Oakey, R. J., Caron, M. G., Lefkowitz, R. J., Seldin, M. F. Genomic organization of adrenergic and serotonin receptors in the mouse: linkage mapping of sequence-related genes provides a method for examining mammalian chromosome evolution. Genomics 10: 338-344, 1991. [PubMed: 1676978, related citations] [Full Text]

  7. Ramarao, C. S., Denker, J. M., Perez, D. M., Gaivin, R. J., Riek, R. P., Graham, R. M. Genomic organization and expression of the human alpha-1B-adrenergic receptor. J. Biol. Chem. 267: 21936-21945, 1992. [PubMed: 1328250, related citations]

  8. Yang-Feng, T. L., Xue, F., Zhong, W., Cotecchia, S., Frielle, T., Caron, M. G., Lefkowitz, R. J., Francke, U. Chromosomal organization of adrenergic receptor genes. Proc. Nat. Acad. Sci. 87: 1516-1520, 1990. [PubMed: 2154750, related citations] [Full Text]


Victor A. McKusick - updated : 9/17/1998
Victor A. McKusick - updated : 11/13/1997
Creation Date:
Victor A. McKusick : 12/2/1987
carol : 03/11/2022
carol : 09/30/2014
carol : 9/21/1998
terry : 9/17/1998
terry : 11/13/1997
terry : 11/13/1997
carol : 11/10/1994
pfoster : 8/16/1994
jason : 6/16/1994
carol : 11/16/1993
carol : 11/5/1993
carol : 1/15/1993

* 104220

ALPHA-1B-ADRENERGIC RECEPTOR; ADRA1B


Alternative titles; symbols

ALPHA-1-ADRENERGIC RECEPTOR; ADRA1


HGNC Approved Gene Symbol: ADRA1B

Cytogenetic location: 5q33.3     Genomic coordinates (GRCh38): 5:159,865,086-159,989,205 (from NCBI)


TEXT

Description

Adrenergic receptors belong to the superfamily of G protein-coupled 7-transmembrane domain receptors. In response to external catecholamine stimuli, these receptors mediate a variety of cellular processes such as cardiac and atrial smooth muscle contraction (summary by Ramarao et al., 1992).


Cloning and Expression

Using the hamster Adra1b sequence to screen a heart cDNA library, Ramarao et al. (1992) cloned the human alpha-1B-adrenergic receptor. The deduced protein contains 517 amino acids and has a molecular mass of 56.7 kD. The human and mouse protein sequences share 98% homology. Northern blot analysis identified 2.8-kb ADRA1B transcripts predominantly in heart but also in kidney and brain.


Gene Structure

Ramarao et al. (1992) found that the ADRA1B gene comprises 2 exons and a single large intron of at least 20 kb that interrupts the coding region at the end of the putative sixth transmembrane domain. The genomic organization of this adrenergic receptor with a single large intron interrupting its coding region differs from those of previously described adrenergic receptors as well as muscarinic and 5-hydroxytryptamine receptors, which are intronless. The location of the intron is also unique among those members of the G protein-coupled receptor family that do possess introns.


Mapping

Yang-Feng et al. (1990) mapped the ADRA1 gene to chromosome 5 by Southern analysis of somatic cell hybrids and regionalized it to 5q32-q34 by in situ hybridization. From pulsed field gel electrophoresis, they concluded that the ADRA1R and ADRB2R (109690) loci are within 300 kb of each other. Lomasney et al. (1991) indicated that this alpha-1 receptor is alpha-1B and that the regional assignment is 5q23-q32. The corresponding gene in the mouse, symbolized Adra1r, is located on proximal chromosome 11 (Oakey et al., 1991).

Loftus et al. (1994) concluded that ADRA1B and ADRB2 are several Mb apart rather than a few hundred kb as reported by Yang-Feng et al. (1990).


Gene Function

When transfected into NIH 3T3 fibroblasts and other cell lines, the alpha-1B-adrenergic receptor induces neoplastic transformation which identifies this normal cellular gene as a protooncogene. Allen et al. (1991) demonstrated that mutational alteration of the receptor can lead to activation of this protooncogene in such a way that cell lines are constitutively activated, even though not stimulated by agonist. These cells demonstrate an enhanced ability for tumor generation in nude mice, with a decreased period of latency compared with cells expressing the wildtype receptor. From these observations, Allen et al. (1991) suggested that analogous spontaneously occurring mutations in this class of receptor proteins could play a key role in the induction or progression of neoplastic transformation and atherosclerosis. Indeed, a comparable situation was demonstrated in the case of the thyrotropin receptor, causing hyperfunctioning thyroid adenoma (275200.0002). Furthermore, a mutation in the luteinizing hormone receptor can result in its constitutive activation, resulting in familial male precocious puberty (152790.0001).


Molecular Genetics

The distal end of 5q, 5q31.1-qter, contains the genes for 2 adrenergic receptors, ADRB2 (109690) and ADRA1B, and the dopamine receptor type 1A gene (DRD1A; 126449). Krushkal et al. (1998) used an efficient discordant sib-pair ascertainment scheme to investigate the impact of this region of the genome on variation in systolic blood pressure in young Caucasians. They measured 8 highly polymorphic markers spanning this positional candidate gene-rich region in 427 individuals from 55 3-generation pedigrees containing 69 discordant sib pairs, and calculated multipoint identity by descent probabilities. The results of genetic linkage and association tests indicated that the region between markers D5S2093 and D5S462 was significantly linked to 1 or more polymorphic genes influencing interindividual variation in systolic blood pressure levels. Since the ADRA1B and DRD1A genes are located close to these markers, the data suggested that genetic variation in 1 or both of these G protein-coupled receptors, which participate in the control of vascular tone, plays an important role in influencing interindividual variation in systolic blood pressure levels.


Animal Model

Cavalli et al. (1997) used a gene targeting approach to create a mouse model lacking the alpha-1b-AR. Total alpha-1-AR sites were decreased by 98% in liver, 74% in heart, and 42% in cerebral cortex in alpha-lb-AR -/- mice as compared with +/+ mice. Because of the large decrease of alpha-1-AR in the heart and the loss of the ADRA1B mRNA in the aorta of the -/- mice, the in vivo blood pressure and in vitro aorta contractile responses to alpha-1-agonists were investigated in +/+ and -/- mice. The findings provided strong evidence that this receptor is a mediator of the blood pressure and aorta contractile responses induced by alpha-1 agonists. This was demonstrated by the finding that the mean arterial pressure response to phenylephrine was decreased by 45% in -/- mice as compared with +/+ mice. In addition, phenylephrine-induced contractions of aortic rings also were decreased by 25% in -/- mice.


REFERENCES

  1. Allen, L. F., Lefkowitz, R. J., Caron, M. G., Cotecchia, S. G-protein-coupled receptor genes as protooncogenes: constitutively activating mutation of the alpha-1B-adrenergic receptor enhances mitogenesis and tumorigenicity. Proc. Nat. Acad. Sci. 88: 11354-11358, 1991. [PubMed: 1662393] [Full Text: https://doi.org/10.1073/pnas.88.24.11354]

  2. Cavalli, A., Lattion, A.-L., Hummler, E., Nenniger, M., Pedrazzini, T., Aubert, J.-F., Michel, M. C., Yang, M., Lembo, G., Vecchione, C., Mostardini, M., Schmidt, A., Beermann, F., Cotecchia, S. Decreased blood pressure response in mice deficient of the alpha(1b)-adrenergic receptor. Proc. Nat. Acad. Sci. 94: 11589-11594, 1997. [PubMed: 9326654] [Full Text: https://doi.org/10.1073/pnas.94.21.11589]

  3. Krushkal, J., Xiong, M., Ferrell, R., Sing, C. F., Turner, S. T., Boerwinkle, E. Linkage and association of adrenergic and dopamine receptor genes in the distal portion of the long arm of chromosome 5 with systolic blood pressure variation. Hum. Molec. Genet. 7: 1379-1383, 1998. [PubMed: 9700190] [Full Text: https://doi.org/10.1093/hmg/7.9.1379]

  4. Loftus, S. K., Shiang, R., Warrington, J. A., Bengtsson, U., McPherson, J. D., Wasmuth, J. J. Genes encoding adrenergic receptors are not clustered on the long arm of human chromosome 5. Cytogenet. Cell Genet. 67: 69-74, 1994. [PubMed: 8039425] [Full Text: https://doi.org/10.1159/000133802]

  5. Lomasney, J. W., Cotecchia, S., Lorenz, W., Leung, W.-Y., Schwinn, D. A., Yang-Feng, T. L., Brownstein, M., Lefkowitz, R. J., Caron, M. G. Molecular cloning and expression of the cDNA for the alpha-1A-adrenergic receptor: the gene for which is located on human chromosome 5. J. Biol. Chem. 266: 6365-6369, 1991. [PubMed: 1706716]

  6. Oakey, R. J., Caron, M. G., Lefkowitz, R. J., Seldin, M. F. Genomic organization of adrenergic and serotonin receptors in the mouse: linkage mapping of sequence-related genes provides a method for examining mammalian chromosome evolution. Genomics 10: 338-344, 1991. [PubMed: 1676978] [Full Text: https://doi.org/10.1016/0888-7543(91)90317-8]

  7. Ramarao, C. S., Denker, J. M., Perez, D. M., Gaivin, R. J., Riek, R. P., Graham, R. M. Genomic organization and expression of the human alpha-1B-adrenergic receptor. J. Biol. Chem. 267: 21936-21945, 1992. [PubMed: 1328250]

  8. Yang-Feng, T. L., Xue, F., Zhong, W., Cotecchia, S., Frielle, T., Caron, M. G., Lefkowitz, R. J., Francke, U. Chromosomal organization of adrenergic receptor genes. Proc. Nat. Acad. Sci. 87: 1516-1520, 1990. [PubMed: 2154750] [Full Text: https://doi.org/10.1073/pnas.87.4.1516]


Contributors:
Victor A. McKusick - updated : 9/17/1998
Victor A. McKusick - updated : 11/13/1997

Creation Date:
Victor A. McKusick : 12/2/1987

Edit History:
carol : 03/11/2022
carol : 09/30/2014
carol : 9/21/1998
terry : 9/17/1998
terry : 11/13/1997
terry : 11/13/1997
carol : 11/10/1994
pfoster : 8/16/1994
jason : 6/16/1994
carol : 11/16/1993
carol : 11/5/1993
carol : 1/15/1993