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(Circulation Research. 2001;89:641.)
© 2001 American Heart Association, Inc.

Editorials

PI3King the L-Type Calcium Channel Activation Mechanism

Susan F. Steinberg

From the Departments of Pharmacology and Medicine, College of Physicians and Surgeons, Columbia University, New York, NY.

Correspondence to Susan F. Steinberg, MD, Associate Professor of Pharmacology and Medicine, Department of Pharmacology, College of Physicians and Surgeons, Columbia University, 630 W 168 St, New York, NY 10032. E-mail sfs1@columbia.edu

Key Words: PI3-kinase • calcium channels • G proteins • tyrosine kinases

In recent years, class I phosphoinositide 3-kinases (PI3Ks) have been implicated in an increasing number of signal transduction pathways linking virtually every class of extracellular stimulus to intracellular response.^1–3 Class I PI3Ks are enzymes that selectively phosphorylate the 3'-OH position of the PtdIns(4,5)P₂ inositol ring in vivo to generate PtdIns(3,4,5)P₃, which then can be further metabolized by inositol lipid phosphatases to PtdIns(3,4)P₂. PtdIns(3,4)P₂ and PtdIns(3,4,5)P₃ are nominally absent in resting cells, rise briskly in response to class I PI3K activation during cellular stimulation, and function in signal transduction and membrane trafficking largely as a result of their interaction with pleckstrin homology (PH) domains (100 amino acid 3-phosphoinositide binding modules) in a range of cellular proteins. Class I PI3Ks have been subclassified further according to their structure and mode of activation by cell surface receptors (Figure, panel A). Class I_A PI3Ks are heterodimers composed of a catalytic subunit (the ubiquitous p110, more tissue-restricted p110ß, or p110 which is confined to hematopoietic cells) tightly complexed to a regulatory adapter subunit (p85, p85ß, p55, or their splice variants). All catalytic subunits bind Ras, but the role of this interaction in PI3K signaling is uncertain. Regulatory subunits harbor a C-terminal p110-binding region flanked by two SH2 domains that dock the holoenzyme to the membrane through interactions with specific phosphotyrosyl-containing sequences within the C-terminus of receptor tyrosine kinases or other membrane-associated proteins. Larger p85 regulatory subunits also contain a series of N-terminal modular domains that specify other protein-protein . . . [Full Text of this Article]

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