Activation of cGMP-dependent protein kinase Iα and cAMP-dependent protein kinase A isoforms by cyclic nucleotides

Abstract

cAMP and cGMP are second messengers that play important roles in intracellular signal transduction of various external stimuli. Major functions of both are the activation of cAMP-dependent protein kinase A (PKA) and cGMP-dependent protein kinase G (PKG), respectively. PKA and PKG are members of the serine-threonine protein kinase superfamily and are involved in the control of various cellular processes. PKA exists as an inactive tetramer of two regulatory (R) and two catalytic (C) subunits that dissociate in the presence of cAMP [1]. PKG is a polypeptide composed of a regulatory domain which contains two tandem cGMP–binding sites that interact allosterically and a catalytic domain [2]. Binding of cGMP to the regulatory domain increases the phosphotransferase activity of PKG. Besides cAMP and cGMP, other cyclic nucleotides can tentatively function as second messengers. As shown by Desch et al. [3], the membrane-permeable cCMP-analogue dibutyryl-cCMP induces smooth muscle relaxation and activates PKGI in aortic tissue lysates by using the cGMP signal transduction pathway. Therefore, we have searched for further binding proteins by using cCMP-agaroses and cCMP-capture compounds, and we have identified the regulatory subunits of PKA as cCMP-interacting proteins.