Cardiac cAMP Microdomains and Their Modulation Using Disruptor Peptides

PDEs are an important superfamily of enzymes that regulate dynamic gradients of cyclic nucleotides. The plethora of isoforms that can be generated from the 11 families are selectively expressed and targeted in cellular microdomains, with each isoform’s function underpinned by its location, affinity/specificity of its cyclic nucleotide substrate, and ability to be modified by posttranslational modifications. The best way to define the function of a particular “pool” of PDE within a cell is to displace the active protein from its site of action. As many PDE isoforms have multiple functions within the same or closely related cell types, pharmacological inhibition, silencing with siRNA, or dominant negative approaches can only reveal functional changes that are a product of the attenuation of the activity of an isoform in all its possible locations. To allow a more detailed appreciation of the role of cyclic nucleotide signaling in cellular microdomains, peptides directed at sequences that serve to anchor individual enzymes to discrete cellular locations have been devised to displace endogenous, active PDE “pools.” As this approach is not directed at the active site of the PDE, global PDE activity within the cell remains unaltered, while confined microdomains experience increases in cyclic nucleotide concentration that may alter PKA-directed modifications of local substrates or promote inappropriate EPAC activation. This chapter reviews recent developments in the disruption of cAMP signalosomes using specific disruptor peptides.