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(Circulation Research. 2002;91:1.)
© 2002 American Heart Association, Inc.

Editorials

TRPC4 Knockout Mice

The Coming of Age of TRP Channels as Gates of Calcium Entry Responsible for Cellular Responses

Lutz Birnbaumer

From the Transmembrane Signaling Group, Laboratory of Signal Transduction, and Division of Intramural Research, National Institute of Environmental Health Sciences, Research Triangle Park, NC.

Correspondence to Lutz Birnbaumer, PhD, Bldg 101, Room A-214, 111 T.W. Alexander Dr, Research Triangle Park, NC 27709. E-mail lutzb@niehs.nih.gov

Key Words: transient receptor potential • I_CRAC • calcium signaling • phospholipase • endothelial cell function

An extract of the first 250 words of the full text is provided, because this article has no abstract.

In this issue of Circulation Research, Tiruppathi and collaborators present a second report on the phenotypic changes that develop in mice lacking the TRPC4 channels developed by the Flockerzi group at the Institute for Pharmacology and Toxicology of the University of Saarland, Germany.¹ This and the earlier report² show unequivocally that TRPC channels and the Ca²⁺ whose entry they mediate are central players in cellular and organismic homeostasis.

Increases in cytosolic Ca²⁺ drive a myriad of cellular responses to extracellular stimuli, either alone or in conjunction with other signaling pathways. Examples are skeletal and smooth muscle contraction, neuronal and endocrine secretions, and activation of B and T lymphocytes, of neutrophil chemotaxis, of endothelial cell NO production, and of platelet aggregation. With the exception of skeletal muscle contraction, which is mediated exclusively by Ca²⁺ released from the sarcoplasmic reticulum in response to sarcolemmal depolarization, all other cellular responses enabled by Ca²⁺ depend on Ca²⁺ entering from the extracellular space through Ca²⁺-permeable ion channels. True to this adage, cardiac and smooth muscle contraction and neuro-, endo-, and exocrine secretions fail upon removal of extracellular Ca²⁺. Cells are negatively affected by sustained high cytosolic Ca²⁺ ([Ca²⁺]_i) and expend significant amounts of energy to keep [Ca²⁺]_i at low, 100 nmol/L levels—10⁴ times lower than present in the extracellular milieu. Entry of Ca²⁺ into cells is thus carefully gated. The gating is performed by just three classes of ion channels: (1) voltage-gated Ca²⁺ channels, structural relatives of voltage-gated sodium . . . [Full Text of this Article]

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