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The regulation of the cGMP-binding cGMP phosphodiesterase by proteins that are immunologically related to gamma subunit of the photoreceptor cGMP phosphodiesterase

Lochhead, A and Nekrasova, E and Arshavsky, V Y and Pyne, N J (1997) The regulation of the cGMP-binding cGMP phosphodiesterase by proteins that are immunologically related to gamma subunit of the photoreceptor cGMP phosphodiesterase. Journal of Biological Chemistry, 272 (29). pp. 18397-18403. ISSN 0021-9258

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Abstract

The cGMP phosphodiesterase from retinal rods (PDE-6) is an alphabetagamma2 heterotetramer. The alpha and beta subunits contain catalytic sites for cGMP hydrolysis, whereas the gamma subunits serve as a protein inhibitor of the enzyme. Visual excitation of photoreceptors enables the activated GTP-bound form of the G-protein transducin to remove the inhibitory action of the gamma subunit, thereby triggering PDE-6 activation. The type 5 phosphodiesterase (PDE-5) isoform shares a number of similar characteristics with PDE-6, including binding of cGMP to noncatalytic sites, the cyclic nucleotide specificity, and inhibitor sensitivities. Although the functional role of PDE-5 remains unclear, it has been shown to be activated by protein kinase A (PKA) (Burns, F., Rodger, I. W. & Pyne, N. J. (1992) Biochem. J. 283, 487-491). Here we report that both the recombinant gamma subunit and a peptide corresponding to amino acids 24-46 in this protein inhibited the activation of PDE-5 by PKA. Furthermore, immunoblotting airway smooth muscle membranes with a specific antibody against amino acids 24-46 of the PDE-6 gamma subunit identified two major immunoreactive small molecular mass proteins of 14 and 18 kDa (p14 and p18). These appear to form a complex with PDE-5, because PDE activity was immunoprecipitated using antibody against the PDE-6 gamma subunit. p14 and p18 were also substrates for phosphorylation by a unidentified kinase that was stimulated by a pertussis toxin-sensitive G-protein. Phosphorylation of p14/p18 in membranes treated with guanine nucleotides correlated with a concurrent reduction in the activation of PDE-5 by PKA. We suggest that p14 and p18 share an epitope common to PDE-6 gamma and that this region may interact with PDE-5 to prevent its activation by PKA.

Item type: Article
ID code: 34935
Keywords: 3',5'-cyclic-GMP phosphodiesterases, adenosine triphosphate, animals, antibodies, binding sites, cell membrane, cells, cultured, cyclic AMP-dependent protein kinases, cyclic GMP, cyclic nucleotide phosphodiesterases, type 5, GTP-binding proteins, guanylyl imidodiphosphate, guinea pigs, homeostasis, kinetics, lung, macromolecular substances, muscle, smooth, pertussis toxin, phosphoric diester hydrolases, recombinant proteins, retinal rod photoreceptor cells, trachea, virulence factors, bordetella, Pharmacy and materia medica
Subjects: Medicine > Pharmacy and materia medica
Department: Faculty of Science > Strathclyde Institute of Pharmacy and Biomedical Sciences
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    Depositing user: Pure Administrator
    Date Deposited: 15 Nov 2011 15:24
    Last modified: 12 Mar 2012 11:37
    URI: http://strathprints.strath.ac.uk/id/eprint/34935

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