Pharmacological PKA Inhibition: All May Not Be What It Seems

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Science Signaling  03 Jun 2008:
Vol. 1, Issue 22, pp. re4
DOI: 10.1126/scisignal.122re4


  • Fig. 1.

    Summary of the cAMP signaling cascade. cAMP is produced from ATP by adenylyl cyclase and is broken down by phosphodiesterases to 5′ AMP. Adenylyl cyclase activity can be modulated by agonist binding at GPCRs. cAMP acts directly on three targets: PKA, Epac, and CNGCs. These in turn regulate various cellular processes both directly and through intermediaries. For clarity, a number of pathways mediated by PKA, Epac, and Rap1 have been omitted. These pathways are discussed more fully in (1, 6, 8, 9, 63). AKAP, A-kinase anchoring protein; ATF1, activating transcription factor 1; C, protein kinase A catalytic subunit; cAMP, cyclic adenosine monophosphate; CNGC, cyclic nucleotide–gated ion channel; CREB, cAMP response element–binding protein; CREM, cAMP response element modulator; ERK1/2, extracellular signal–related kinase 1/2; JNK, Jun N-terminal kinase; PDE, phosphodiesterases; PKA, protein kinase A; R, protein kinase A regulatory subunit

  • Fig. 2.

    Activation of PKA by cAMP. In its inactive state, PKA consists of a tetramer of two regulatory and two catalytic subunits. Each regulatory subunit has two cAMP-binding sites; cAMP binding releases the catalytic subunits, which become bound to ATP and go on to phosphorylate serine and threonine residues that possess the appropriate substrate sequence. The two cAMP-binding sites (A and B) on each regulatory subunit are shown. C, protein kinase A catalytic subunit; R, protein kinase A regulatory subunit.

  • Fig. 3.

    Mechanisms of actions of PKA inhibitors. (A) Rp-cAMPS is a competitive antagonist of the cAMP-binding sites on PKA; binding of Rp-cAMPS to PKA prevents the catalytic subunits from being released. PKI peptide, H89, and KT 5720 all act one stage later. After cAMP binding and catalytic subunit release, PKI peptide binds the catalytic subunits and prevents them from phosphorylating targets. (B) H89 and KT 5720 are both competitive antagonists of the ATP sites on the catalytic subunits; without ATP binding, the catalytic subunits are unable to phosphorylate target proteins. C, protein kinase A catalytic subunit; PKI, protein kinase inhibitor peptide; R, protein kinase A regulatory subunit.

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