Alternative splicing regulates the subcellular localization of A-kinase anchoring protein 18 isoforms

The cAMP-dependent protein kinase (PKA) is localized to specific subcellula r compartments by association with A-kinase anchoring proteins (AKAPs), AKA Ps are a family of functionally related proteins that bind the regulatory ( R) subunit of PKA with high affinity and target the kinase to specific subc ellular organelles. Recently, AKAP18, a low molecular weight plasma membran e AKAP that facilitates PKA-mediated phosphorylation of the L-type Ca2+ cha nnel, was cloned. We now report the cloning of two additional isoforms of A KAP18, which we have designated AKAP18 beta and AKAP18 gamma, that arise fr om alternative mRNA splicing. The AKAP18 isoforms share a common R subunit binding site, but have distinct targeting domains. The original AKAP18 (ren amed AKAP18 alpha) and AKAP18 beta target the plasma membrane when expresse d in HEK-293 cells, while AKAP18 gamma is cytosolic. When expressed in epit helial cells, AKAP18 alpha is targeted to lateral membranes, whereas AKAP18 beta is accumulated at the apical membrane. A 23-amino acid insert, follow ing the plasma membrane targeting domain, facilitates the association of AK AP18 beta with the apical membrane. The data suggest that AKAP18 isoforms a re differentially targeted to modulate distinct intracellular signaling eve nts. Furthermore, the data suggest that plasma membrane AKAPs may be target ed to subdomains of the cell surface, adding additional specificity in intr acellular signaling.