Competitive regulation of CaT-like-mediated Ca2+ entry by protein kinase C and calmodulin.
A finely tuned Ca(2+) signaling system is essential for cells to transduce extracellular stimuli, to regulate growth, and to differentiate. We have recently cloned CaT-like (CaT-L), a highly selective Ca(2+) channel closely related to the epithelial calcium channels (ECaC) and the calcium transport protein CaT1. CaT-L is expressed in selected exocrine tissues, and its expression also strikingly correlates with the malignancy of prostate cancer. The expression pattern and selective Ca(2+) permeation properties suggest an important function in Ca(2+) uptake and a role in tumor progression, but not much is known about the regulation of this subfamily of ion channels. We now demonstrate a biochemical and functional mechanism by which cells can control CaT-L activity. CaT-L is regulated by means of a unique calmodulin binding site, which, at the same time, is a target for protein kinase C-dependent phosphorylation. We show that Ca(2+)-dependent calmodulin binding to CaT-L, which facilitates channel inactivation, can be counteracted by protein kinase C-mediated phosphorylation of the calmodulin binding site.
Institut für Pharmakologie und Toxikologie der Universität des Saarlandes, 66421 Homburg, Germany.
B A
BA
Niemeyer
C
C
Bergs
U
U
Wissenbach
V
V
Flockerzi
C
C
Trost
D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D016466:CHO Cells; D002118:Calcium / Q000378:metabolism; D015220:Calcium Channels / Q000235:genetics / Q000378:metabolism*; D002135:Calcium-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D002147:Calmodulin / Q000378:metabolism; D002460:Cell Line; D006224:Cricetinae; D006801:Humans; D008969:Molecular Sequence Data; D010766:Phosphorylation; D011493:Protein Kinase C / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D050916:TRPV Cation Channels
D015220:Calcium Channels; D002135:Calcium-Binding Proteins; D002147:Calmodulin; D011993:Recombinant Fusion Proteins; D050916:TRPV Cation Channels; C120776:TRPV6 channel; D011493:Protein Kinase C; D002118:Calcium