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The cAMP-dependent protein kinase (PKA) is localized to specific subcellular compartments by association with A-kinase anchoring proteins (AKAPs). AKAPs are a family of functionally related proteins that bind the regulatory (R) subunit of PKA with high affinity and target the kinase to specific subcellular organelles. Recently, AKAP18, a low molecular weight plasma membrane AKAP that facilitates PKA-mediated phosphorylation of the L-type Ca(super 2+) channel, was cloned. We now report the cloning of two additional isoforms of AKAP18, which we have designated AKAP18(beta) and AKAP18(gamma), that arise from alternative mRNA splicing. The AKAP18 isoforms share a common R subunit binding site, but have distinct targeting domains. The original AKAP18 (renamed AKAP18(alpha)) and AKAP18(beta) target the plasma membrane when expressed in HEK-293 cells, while AKAP18(gamma)is cytosolic. When expressed in epithelial cells, AKAP18(alpha) is targeted to lateral membranes, whereas AKAP18(beta) is accumulated at the apical membrane. A 23-amino acid insert, following the plasma membrane targeting domain, facilitates the association of AKAP18(beta) with the apical membrane. The data suggest that AKAP18 isoforms are differentially targeted to modulate distinct intracellular signaling events. Furthermore, the data suggest that plasma membrane AKAPs may be targeted to subdomains of the cell surface, adding additional specificity in intracellular signaling.