Disease relevance of Pkg21D

• Perturbing components of the NO/cGMP pathway altered both tracheal development and survival during prolonged hypoxia [1].
• This manifests itself as hypersensitivity of epithelial fluid transport to the nitridergic neuropeptide, capa-1, which acts through nitric oxide and cGMP [2].
• There was no evidence that the cAMP system is part of the modulatory mechanism. cGMP is likely to be integral to one active pathway, as non-hydrolyzable forms of this cyclic nucleotide increase heart rate, and flies bearing the mutation sitter, a recessive allele of the foraging gene, which encodes a cGMP-dependent kinase, have tachycardia [3].

High impact information on Pkg21D

• Nitric oxide activates soluble guanylate cyclase in target cells, leading to the formation of cGMP [4].
• These results suggest NO and cGMP act to stabilize retinal growth cones at the start of synaptic assembly [5].
• This antidiuretic factor (ADF) appears to elicit its effect via cGMP as a second messenger but does not stimulate NO production [6].
• The cDNA for a membrane-associated cGMP-dependent protein kinase (cGK II) was cloned from rat intestine using reverse transcriptase PCR and oligonucleotide primers encoding two conserved motifs of known cGMP-dependent protein kinases and subsequently by screening a rat intestine cDNA library [7].
• Activation is specific and it cannot be mimicked by a series of agents that include AMP, cGMP, ATP, inositol trisphosphate, and Ca2+ [8].

Biological context of Pkg21D

• The deduced product of one gene (DG1; cytological position, 21D) is 14% larger than the bovine enzyme and differs substantially in sequence at the amino terminus, the region responsible in the bovine enzyme for dimerization [9].
• A common progenitor of the two cGMP-dependent protein kinase genes, DG1 and DG2, is strongly suggested by the conserved positions of introns in these genes [9].
• The catalytic subunit gene and the cGMP-dependent protein kinase gene have been located in regions 30C and 21D, respectively, of chromosome 2 [10].
• DNA sequence analysis demonstrates that this fragment is part of the cGMP-dependent protein kinase gene or a close homolog [10].
• Tissue distribution of the DG1 kinase was investigated by immunohistochemistry [11].

Anatomical context of Pkg21D

• Analysis of Drosophila cGMP-dependent protein kinases and assessment of their in vivo roles by targeted expression in a renal transporting epithelium [12].
• DG2P1 and DG2P2 were localized in the plasma membrane in S2 cells, whereas DG1 was localized in the cytosol [12].
• The type I cGMP-dependent protein kinase (cGK) has been shown to play a crucial role in the relaxation of vascular smooth muscle by lowering the intracellular level of calcium [13].
• These G proteins, however, activate different photoreceptor enzymes: phospholipase C in invertebrates and cGMP phosphodiesterase in vertebrates [14].
• Application of NO donors induced cGMP immunoreactivity in the presynaptic terminals but not the postsynaptic muscle fibers at an identified NMJ [15].

Associations of Pkg21D with chemical compounds

• The concentrations of cGMP, cAMP, cIMP, 8-bromo-cGMP, and 8-bromo-cAMP that gave 50% activation were 0.19 +/- 0.06, 11.7 +/- 2.8, 5.3 +/- 1.5, 0.04 +/- 0 [11].
• Evidence is mounting that phototransduction in Drosophila and other invertebrate species may additionally involve the second messenger, cyclic-GMP (cGMP) [16].
• The functions of intracellular second messengers, such as guanosine 3'5'-cyclic monophosphate (cGMP), adenosine 3'5'-cyclic monophosphate (cAMP), and intracellular calcium, are thus intensively studied [17].
• Compound 1 is a potent inhibitor of both soluble and membrane-associated isoforms of native PKG, as well as recombinant enzyme, with an IC(50) of <1 nm [18].
• Furthermore, inhibition of PDE5 activity by sildenafil restores basal and cGMP-stimulated fluid transport rates to control levels [19].

Regulatory relationships of Pkg21D

• The regulatory subunit of a cGMP-regulated protein kinase A of Trypanosoma brucei [20].

Other interactions of Pkg21D

• The largest (DG2; T1) and smallest (DG2;T3) RNAs encode overlapping polypeptides of similar sequence to the whole length of bovine lung cGMP-dependent protein kinase [9].
• Two Drosophila genes encoding products related to cGMP-dependent protein kinase have been isolated by cross-hybridization to a Drosophila cAMP-dependent protein kinase catalytic subunit gene [9].
• 01, and 0.62 +/- 0.06 microM, respectively. cGMP activation was cooperative with a Hill coefficient (nH) of 1.28 +/- 0.10, whereas activation by cAMP was not cooperative [11].
• Furthermore, a novel epithelial role is suggested for DG1, which is considerably more responsive to cGMP than to capa-1 stimulation [12].

Analytical, diagnostic and therapeutic context of Pkg21D

• Furthermore, cGMP induces a slow [Ca2+]i increase in tubule principal cells via verapamil- and nifedipine-sensitive calcium entry; RT-PCR shows that tubules express Drosophila cyclic nucleotide-gated channel (cng) [21].

References