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This Article Full Text Full Text (PDF) All Versions of this Article: fj.07-102558v1 22/8/2768    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Grubb, D. R. Articles by Woodcock, E. A. PubMed PubMed Citation Articles by Grubb, D. R. Articles by Woodcock, E. A.

The extreme C-terminal region of phospholipase Cβ1 determines subcellular localization and function; the "b" splice variant mediates ₁-adrenergic receptor responses in cardiomyocytes

Cellular Biochemistry Laboratory, Baker Heart Research Institute, Melbourne, Victoria, Australia

¹Correspondence: Baker Heart Research Institute, P.O. Box 6492, St. Kilda Road Central, Melbourne, 8008, Victoria, Australia. E-mail: liz.woodcock{at}baker.edu.au

Phospholipase Cβ1 (PLCβ1) exists as two splice variants, PLCβ1a (150 kDa) and PLCβ1b (140 kDa), which differ only in their C-terminal sequences of 64 and 31 amino acids, respectively. The 3 C-terminal amino acid residues of PLCβ1a comprise a PDZ-interacting domain, whereas the PLCβ1b sequence has no PDZ-interacting domain but contains unique proline-rich domain 5 residues from the C terminus. PLCβ1a is localized in the cytoplasm, whereas PLCβ1b targets to the sarcolemma and is enriched in caveolae. Deletion of 3 amino acids from the C terminus of PLCβ1b did not alter its sarcolemmal localization, but deletion of the entire unique 31 amino acid sequence caused cytosolic localization. A myristoylated 10 amino acid peptide from the C terminus of PLCβ1b selectively dissociated N-terminally GFP-tagged PLCβ1b from the sarcolemma and inhibited PLC responses to ₁-adrenergic agonists, with a half maximal effective concentration of 12 ± 1.6 µM (mean±SE, n=3). A similar peptide from PLCβ1a was without effect at concentrations below 100 µM. Thus, the extreme C-terminal sequences of the PLCβ1 splice variants determine localization and, thus, function. In cardiomyocytes, responses initiated by ₁-adrenergic receptor activation involve only PLCβ1b, and the selective targeting of this splice variant to the sarcolemma provides a potential therapeutic target to reduce hypertrophy, apoptosis, and arrhythmias.—Grubb, D. R., Vasilevski, O., Huynh, H., and Woodcock, E. A. The extreme C-terminal region of phospholipase Cβ1 determines subcellular localization and function; the "b" splice variant mediates ₁-adrenergic receptor responses in cardiomyocytes.

Key Words: proline-rich domain • Gq • PLC • myristoylated peptides • signaling specificity