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The ion channel TRPV6 is likely to function as an epithelial calcium channel in organs with high calcium transport requirements such as the intestine, kidney, and placenta. Transcriptional regulation of TRPV6 messenger RNA (mRNA) is controlled by 1,25-dihydroxyvitamin D, which is the active hormonal form of vitamin D3, and by additional calcium-dependent and vitamin D3-independent mechanisms. Under physiological conditions, the conductance of the channel itself is highly calcium-selective and underlies complex inactivation mechanisms triggered by intracellular calcium and magnesium ions. There is growing evidence that transcriptional regulation of TRPV6 in certain tissues undergoing malignant transformation, such as prostate cancer, is linked to cancer progression.

Life expectancy for patients suffering from prostate cancer is inversely correlated with the degree of extraprostatic metastasis. In order to find pharmacological tools to treat this aggressive growth it is important to define targets whose expression not only correlates with the malignancy of the cancerous cells, but that are also amenable to pharmacological intervention. In this review, we would like to focus on the potential role of a distinct class of ion channels that may be involved in this process., (Copyright 2004 Elsevier Inc.)

The regulation of intracellular Ca(2+) plays a key role in the development and growth of cells. Here we report the cloning and functional expression of a highly calcium-selective channel localized on the human chromosome 7. The sequence of the new channel is structurally related to the gene product of the CaT1 protein cloned from rat duodenum and is therefore called CaT-like (CaT-L). CaT-L is expressed in locally advanced prostate cancer, metastatic and androgen-insensitive prostatic lesions but is undetectable in healthy prostate tissue and benign prostatic hyperplasia. Additionally, CaT-L is expressed in normal placenta, exocrine pancreas, and salivary glands. New markers with well defined biological function that correlate with aberrant cell growth are needed for the molecular staging of cancer and to predict the clinical outcome. The human CaT-L channel represents a marker for prostate cancer progression and may serve as a target for therapeutic strategies.

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.

Summary: Drosophila phototransduction is a G protein-coupled, calcium-regulated signaling cascade that serves as a model system for the dissection of phospholipase C (PLC) signaling in vivo. The Drosophila light-activated conductance is constituted in part by the transient receptor potential (trp) ion channel, yet trp mutants still display a robust response demonstrating the presence of additional channels. The transient receptor potential-like (trpl) gene encodes a protein displaying 40% amino acid identity with TRP. Mammalian homologs of TRP and TRPL recently have been isolated and postulated to encode components of the elusive I(crac) conductance. We now show that TRP and TRPL localize to the membrane of the transducing organelle, together with rhodopsin and PLC, consistent with a role in PLC signaling during phototransduction. To determine the function of TRPL in vivo, we isolated trpl mutants and characterized them physiologically and genetically. We demonstrate that the light-activated conductance is composed of TRP and TRPL ion channels and that each can be activated on its own. We also use genetic and electrophysiological tools to study the contribution of each channel type to the light response and show that TRP and TRPL can serve partially overlapping functions.