Disease relevance of Prkar1b

• Because the RIbeta subunit is only present in the nervous system, including small diameter trkA receptor-positive dorsal root ganglion cells, we suggest that in inflammatory conditions, RIbeta PKA is specifically required for nociceptive processing in the terminals of small-diameter primary afferent fibers [1].

High impact information on Prkar1b

• In mice there are four R genes (encoding RI alpha, RI beta, RII alpha, and RII beta) and two C gene (encoding C alpha and C beta), expressed in tissue-specific patterns [2].
• Cross-linking of the transgenic Fc epsilon RI with human IgE and antigens led to mast cell activation as indicated by enhanced tyrosine phosphorylation of the Fc epsilon RI beta and gamma chains and other cellular proteins [3].
• These data demonstrate that ARAM gamma is necessary for allowing both receptors to phosphorylate the complete set of substrates, and that the CD3 complex, unlike the Fc epsilon RI beta chain, contains activation modules capable of compensating for the absence of a functional ARAM gamma in generating late signals such as IL-2 release [4].
• Hippocampal long-term depression and depotentiation are defective in mice carrying a targeted disruption of the gene encoding the RI beta subunit of cAMP-dependent protein kinase [5].
• Since the late phase of CA1 LTP also requires PKA but is normal in RI beta mutant mice, our data further suggest that different forms of synaptic plasticity are likely to employ different combinations of regulatory and catalytic subunits [5].

Biological context of Prkar1b

• The mouse chromosomal locus (designated Prkar1b) was determined by interspecific backcross mapping and found to reside on the distal arm of chromosome 5 [6].
• We have combined pharmacologic and genetic approaches to demonstrate that PKA activity is required for both homosynaptic LTD and depotentiation and that a specific neuronal isoform of type I regulatory subunit (RI beta) is essential [5].
• The open reading frame of the RI beta cDNA is 72% identical in nucleotide sequence with the previously cloned RI gene, now referred to as RI alpha [7].
• Promoter sequences in the RI beta subunit gene of cAMP-dependent protein kinase required for transgene expression in mouse brain [8].
• Evidence is presented that the GC-rich proximal promoter is responsible for cell type-specific expression in vivo because RI beta DNA containing as little as 17 base pairs (bp) of 5'-upstream sequence was functional in mouse brain [8].

Anatomical context of Prkar1b

• Brain and spinal cord contained significant levels of RI beta mRNA, testis RNA gave a detectable signal, and all other tissues tested were negative [7].
• RI beta protein produced in 3T3 cells was shown to be functional by its ability to form a cAMP-dependent holoenzyme with the catalytic subunit [7].
• Mice carrying a null mutation in the gene encoding RI beta were established by use of gene targeting in embryonic stem cells [5].
• Expression of a RI beta cDNA in NIH 3T3 cells resulted in the appearance of a RI subunit protein that migrated more slowly than RI alpha after NaDodSO4/PAGE [7].
• A beta-galactosidase fusion gene containing 1.5 kilobases of 5'-nontranscribed RI beta DNA and 2 kilobases of intron 1 was expressed preferentially in the cortex and hippocampus of the brain and within the spinal cord [9].

Associations of Prkar1b with chemical compounds

• Here we present a characterization of the mouse RI beta subunit gene, which in contrast to other subunit genes of cyclic AMP-dependent protein kinase is expressed almost exclusively in neurons [6].
• Holoenzymes containing RI beta Ala and RI beta Ala/Ile gave Ka values which were higher than wild type RI beta, with the double mutant shifting toward the Ka value of RI alpha holoenzymes by about 30% [10].
• Localization of Triton-insoluble cAMP-dependent kinase type RIbeta in rat and mouse brain [11].
• Merlin links to the cAMP neuronal signaling pathway by anchoring the RIbeta subunit of protein kinase A [12].
• Finally, both RIbeta- and catylatic subunit beta1-deficient mice showed normal voluntary consumption of ethanol, indicating that increased ethanol consumption is not a general characteristic associated with deletion of PKA subunits [13].

Physical interactions of Prkar1b

• The functional results also complement the recently reported evidence that Fc gamma RIII can interact with Fc epsilon RI beta-subunits (J. Exp. Med. 175:447, 1992) [14].

Other interactions of Prkar1b

• The native form of RI beta in brain could also be distinguished from RI alpha by its abnormal migration on NaDodSO4/PAGE [7].
• To assess the contribution of PKA to injury-induced inflammation and pain, we evaluated nociceptive responses in mice that carry a null mutation in the gene that encodes the neuronal-specific isoform of the type I regulatory subunit (RIbeta) of PKA [1].
• Regulation of cell type-specific mouse Fc epsilon RI beta-chain gene expression by GATA-1 via four GATA motifs in the promoter [15].
• Homology comparisons among these molecules reveal limited regions of homology between Fc epsilon RI beta and Ly-44 (CD20) as well as other striking similarities: both molecules have four putative transmembrane segments and a probably topology where both amino- and carboxytermini protrude into the cytoplasm [16].

Analytical, diagnostic and therapeutic context of Prkar1b

• Ablation by gene targeting of the C beta 1 or the RI beta isoform of PKA produces a selective defect in mossy fiber LTP, providing genetic evidence for the role of these isoforms in the mossy fiber pathway [17].
• Molecular cloning, cDNA structure and tissue-specific expression of the human regulatory subunit RI beta of cAMP-dependent protein kinases [18].
• By immunohistochemistry, the distribution of the detergent-insoluble fraction of RIbeta isoform has been examined in rat and mouse brain [11].
• By using a pH gradient for isoelectric focussing that allowed for clear focussing of 8-N3[32P]cAMP-labeled recombinant RI beta, 8-N3[32P]cAMP-labeled RI beta was readily detected by two-dimensional gel electrophoresis in rat brain particulate extracts and exhibited a pI equivalent to that of recombinant RI beta [19].

References