BBB seminar: Stein Ove Døskeland
cAMP receptors – a fine-tuned orchestra of PKA and Epac isoforms essential for human life
Stein Ove Døskeland
Department of Biomedicine, University of Bergen
The archetypical second messenger cAMP acts through the cAMP-dependent protein kinase (PKA) and the small GTP-ase stimulators Epac1 and Epac2. Epac is expressed only in multicellular organisms, where it fine-tunes the actions of PKA. A number of drugs, including b-receptor stimulators and antagonists, and some novel thrombocyte-directed drugs, target cAMP production or degradation and will therefore act by modulating the activity of PKA, Epac or both.
The catalytic activity of PKA resides in a C subunit, which is controlled by a separate cAMP-binding R subunit. All other protein kinases have R and C domains in the same protein chain. The unique PKA arrangement allows numerous combinations of its 4 R (RIa, RIb, RIIa, RIIb) and 3 C (Ca, Cb, Cg) forms. This redundancy can explain why mice with deleted RIb, RIIa, RIIb or Cb have only subtle, mainly neural, phenotypes. Rare diseases like the “Carney complex” and “acrodysostosis 1” are linked to PKA-activating and PKA-inactivating mutations of the RIa subunit of PKA, respectively, while a new type of “macrothrombocytopenia” is linked to an inactivating Cg mutation.
The talk will cover our development and use of: 1) cell-permeable cAMP analogs that can distinguish between PKA isoforms and between PKA and Epac; 2) Epac1 and Epac2 “KO” mice that revealed Epac functions in the intact organism.
Data will also be presented on cAMP binding and its coupling to activity for PKA isoforms, which allows full modeling of the kinase activity of any combination of R and C subunits of PKA, both in cell cytoplasm and in cell compartments with anchored PKA.
Chairperson: Aurora Martinez, Department of Biomedicine