Alternative titles; symbols
HGNC Approved Gene Symbol: PRKAR2B
Cytogenetic location: 7q22.3 Genomic coordinates (GRCh38): 7:107,044,705-107,161,811 (from NCBI)
The cAMP-dependent protein kinase system is believed to mediate most, if not all, cellular effects of the second messenger cAMP. The kinase holoenzyme consists of 2 regulatory (R) and 2 catalytic (C) subunits that dissociate upon the binding of 2 cAMP molecules to each of the R subunits. The free, activated C subunits then catalyze the phosphorylation of specific substrate proteins on serine and threonine residues and thereby alter their activity or function. PRKAR2B is 1 of several R subunits (Levy et al., 1988).
Using rat Prkar2b as probe, Levy et al. (1988) cloned PRKAR2B, which they designated RII-beta, from a human testis cDNA library. The deduced 418-amino acid protein has a calculated molecular mass of about 54 kD. PRKAR2B contains an N-terminal dimerization domain, an autophosphorylation site (ser114), and 7 potential polyadenylation signals. The human and rat proteins share 97% homology. Northern blot analysis revealed a 3.3-kb transcript expressed at highest levels in testis, fallopian tubes, and ovary. Low or undetectable levels were found in myocardium, parotid gland, parotid tumor, epididymis, uterus, placenta, and umbilical cord. Northern blot analysis also detected cAMP-stimulated Prkar2b expression in rat Sertoli cell cultures.
Levy et al. (1988) estimated the size of the PRKAR2B gene to be close to 28 kb.
Using both a rat skeletal muscle clone and a human clone of type II regulatory subunit of cyclic AMP-dependent protein kinase, Scambler et al. (1987) demonstrated that the human gene is located on chromosome 7, close to but separate from the cystic fibrosis locus (219700). These conclusions were based on Southern blot analysis of DNA from hybrid cell lines containing only chromosome 7 or parts thereof, as well as human/mouse hybrid cell lines established by means of chromosome-mediated gene transfer (CMGT) using MET (164860) as a dominant selectable marker. Independence of PKR2 from CF was also indicated by family linkage studies using a RFLP of the PKR2 probe. Wainwright et al. (1987) showed that PKR2 is linked to several markers on 7q. The closest and strongest linkage was to TCRB (see 186930), which showed a maximum lod score of 3.01 at theta = 0.00.
Using RFLPs in the CEPH panel of 40 families, Solberg et al. (1992) mapped the regulatory subunit RII-beta of cAMP-dependent protein kinase to 7q. They constructed a 7-point framework map including PRKAR2B and demonstrated the following order: cen--D7S371--(COL1A2, D7S79)--PRKAR2B--MET--D7S87--TCRB--qter. Furthermore, by in situ hybridization to metaphase chromosomes, Solberg et al. (1992) physically mapped PRKAR2B to 7q22.
Crystal Structure
Zhang et al. (2012) described the 2.3-angstrom structure of full-length tetrameric RII-beta(2):catalytic subunit-alpha(2) (see 601639) holoenzyme. The structure showing a dimer of dimers provided a mechanistic understanding of allosteric activation by cAMP. The heterodimers are anchored together by an interface created by the beta-4/beta-5 loop in the RII-beta subunit, which docks onto the carboxyl-terminal tail of the adjacent C subunit, thereby forcing the C subunit into a fully closed conformation in the absence of nucleotide. Diffusion of magnesium ATP into these crystals trapped not ATP but the reaction products adenosine diphosphate and the phosphorylated RII-beta subunit. This complex has implications for the dissociation-reassociation cycling of PKA. The quaternary structure of the RII-beta tetramer differs appreciably from the model of the RI-alpha tetramer, confirming the small-angle x-ray scattering prediction that the structures of each PKA tetramer are different.
Cummings et al. (1996) generated knockout mice for the cyclic AMP dependent protein kinase regulatory subunit type II-beta (designated RII-beta by them). They reported that the mutants appeared healthy but had markedly diminished white adipose tissue despite normal food intake and were protected against developing diet-induced obesity and fatty livers. In the mutant mice, brown adipose tissue demonstrated a compensatory increase in RI-alpha (188830). Cummings et al. (1996) reported that RII-beta mutants exhibited markedly reduced leptin (164160) mRNA and plasma levels; however, only mild hyperphagia was present.
Mice bearing a targeted disruption of the Prkar2b gene were used by Adams et al. (1997) to evaluate the importance of cAMP-dependent signaling in transducing the effects of haloperidol on striatal gene expression and behavioral responses. In wildtype mice, haloperidol treatment induces the expression of Fos (164810) and neurotensin (162650) in the dorsal lateral region of the striatum and produces an acute cataleptic response that correlates with the motor side effects of haloperidol in humans. However, Adams et al. (1997) did not observe these responses in mice lacking Prka2b. Prkar2b-deficient mice were able to generate a cataleptic response to intracerebral injections of neurotensin, suggesting that the Prkar2b subunit is required to transduce the acute response to haloperidol in both gene expression and behavior.
A chromosomal deletion in agouti lethal yellow (Ay) mice causes ectopic expression of agouti (ASIP; 600201), which is normally expressed in skin. Agouti antagonizes melanocortin-4 receptor (MC4R; 155541) in neurons, resulting in hyperphagia, hypoactivity, and increased fat mass in Ay mice. Czyzyk et al. (2008) found that RII-beta deletion rescued elevated body weight, hyperphagia, and obesity of Ay mice. Partial rescue of these Ay phenotypes was observed in RII-beta heterozygotes.
Adams, M. R., Brandon, E. P., Chartoff, E. H., Idzerda, R. L., Dorsa, D. M., McKnight, G. S. Loss of haloperidol induced gene expression and catalepsy in protein kinase A-deficient mice. Proc. Nat. Acad. Sci. 94: 12157-12161, 1997. [PubMed: 9342379] [Full Text: https://doi.org/10.1073/pnas.94.22.12157]
Cummings, D. E., Brandon, E. P., Planas, J. V., Motamed, K., Idzerda, R. L., McKnight, G. S. Genetically lean mice result from targeted disruption of the RII-beta subunit of protein kinase A. Nature 382: 622-626, 1996. [PubMed: 8757131] [Full Text: https://doi.org/10.1038/382622a0]
Czyzyk, T. A., Sikorski, M. A., Yang, L., McKnight, G. S. Disruption of the RII-beta subunit of PKA reverses the obesity syndrome of agouti lethal yellow mice. Proc. Nat. Acad. Sci. 105: 276-281, 2008. [PubMed: 18172198] [Full Text: https://doi.org/10.1073/pnas.0710607105]
Levy, F. O., Oyen, O., Sandberg, M., Tasken, K., Eskild, W., Hansson, V., Jahnsen, T. Molecular cloning, complementary deoxyribonucleic acid structure and predicted full-length amino acid sequence of the hormone-inducible regulatory subunit of 3-prime-5-prime-cyclic adenosine monophosphate-dependent protein kinase from human testis. Molec. Endocr. 2: 1364-1373, 1988. [PubMed: 2851102] [Full Text: https://doi.org/10.1210/mend-2-12-1364]
Scambler, P., Oyen, O., Wainwright, B., Farrall, M., Law, H.-Y., Estivill, X., Sandberg, M., Williamson, R., Jahnsen, T. Exclusion of catalytic and regulatory subunits of cAMP-dependent protein kinase as candidate genes for the defect causing cystic fibrosis. Am. J. Hum. Genet. 41: 925-932, 1987. [PubMed: 3479018]
Solberg, R., Sistonen, P., Traskelin, A.-L., Berube, D., Simard, J., Krajci, P., Jahnsen, T., de la Chapelle, A. Mapping of the regulatory subunits RI-beta and RII-beta of cAMP-dependent protein kinase genes on human chromosome 7. Genomics 14: 63-69, 1992. [PubMed: 1358799] [Full Text: https://doi.org/10.1016/s0888-7543(05)80284-8]
Wainwright, B., Lench, N., Davies, K., Scambler, P., Kruyer, H., Williamson, R., Jahnsen, T., Farrall, M. A human regulatory subunit of type II cAMP-dependent protein kinase localized by its linkage relationship to several cloned chromosome 7q markers. Cytogenet. Cell Genet. 45: 237-239, 1987. [PubMed: 3691190] [Full Text: https://doi.org/10.1159/000132461]
Zhang, P., Smith-Nguyen, E. V., Keshwani, M. M., Deal, M. S., Kornev, A. P., Taylor, S. S. Structure and allostery of the PKA RII-beta tetrameric holoenzyme. Science 335: 712-716, 2012. [PubMed: 22323819] [Full Text: https://doi.org/10.1126/science.1213979]