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© The Rockefeller University Press, 0021-9525/1999//1481 $5.00
The Journal of Cell Biology, Volume 147, Number 7, , 1999 1481-1492

Original Article

Alternative Splicing Regulates the Subcellular Localization of a-Kinase Anchoring Protein 18 Isoforms



Kevin W. Trottera, Iain D.C. Fraserb, Gregory K. Scottb, M. Jackson Stuttsc, John D. Scottb, and Sharon L. Milgrama

a Department of Cell and Molecular Physiology, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599
b Howard Hughes Medical Institute, Vollum Institute, Portland, OR 97201
c Cystic Fibrosis/Pulmonary Research and Treatment Center, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599
Department of Cell and Molecular Physiology, University of North Carolina at Chapel Hill, CB 7545, Chapel Hill, NC 27599.(919) 966-6927(919) 966-9792

milg{at}med.unc.edu

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 Ca2+ channel, was cloned. We now report the cloning of two additional isoforms of AKAP18, which we have designated AKAP18β 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 AKAP18β 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 AKAP18β is accumulated at the apical membrane. A 23-amino acid insert, following the plasma membrane targeting domain, facilitates the association of AKAP18β 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.

Key Words: protein kinase A • AKAP • epithelia • targeting • green fluorescent protein

© 1999 The Rockefeller University Press

Kevin W. Trotter and Iain D.C. Fraser contributed equally to this work.

Abbreviations used in this paper: AKAP, A-kinase anchoring protein; C, catalytic; nt, nucleotides; PKA, cAMP-dependent protein kinase; R, regulatory; RII, type II R subunit; RT, reverse transcriptase.


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