TRP channels as potential drug targets

Abstract

Calcium (Ca 2+ ) is an ubiquitous intracellular signal that is responsible for a plethora of cellular processes including fertilization, secretion, contraction, neuronal signaling and learning. In addition, changes in intracellular Ca 2+ have been known to influence cell proliferation and differentiation for more than three decades. Recent studies have indicated that members of the transient receptor potential (TRP) family of ion channels which respond to many different modes of stimulation both from within and outside the cell may be a primary mode of cation and Ca 2+ entry into cells and may have roles in growth control. Moreover, changes in the expression of these channels may contribute to certain cancers. In the following, recent results concerning the expression and function of members of this family of ion channels are summarized. General characteristics of TRP channelsTRP channels are a relatively new class of ion channels, named after their seminal member , the Drosophila melanogaster TRP protein. The complex eye of Drosophila trp mutants -unlike wildtype -is unable to sustain a steady-state response during prolonged light stimulation, thus showing a transient receptor potential. Although trp mutants were initially identified in 1969 (Cosens and Manning), the underlying gene defect was not characterized until 1989 (Montell and Rubin) and identified as an ion channel in 1992 (Hardie and Minke). Since then, many new ion channels of the TRP family of channels have been identified exclusively in ophistokonts (animals and fungi) but so far not in green plants, red alges, protists and bacteria. The general topology of TRP channels includes intracellular N-and C-terminal regions of variable length and six transmembrane spanning domains with a pore loop between transmembrane domain 5 and 6. In analogy to voltage gated potassium channels it is thought that four subunits need to assemble to form a functional channel (see also Hoenderop et al. 2003, for architecture of TRPV5 and TRPV6). In contrast to the voltage-gated potassium channel, the fourth transmembrane region of TRP channels does not contain the regular spacing of voltage sensing positively charged amino acids. So far, all identified channels are cation conducting channels. This rapidly growing important family can be subdivided into seven subgroups according to the degree of sequence homology (see Table 1): The classical (or canonical) TRPC-group is most closely related to the seminal Drosophila TRP and includes seven members, the TRPV group, named after their first member, the vanilloid receptor, includes six members and the TRPM group, named after the melastatin gene includes eight members. More distantly related are the TRPP group including one polycystic kidney disease protein (PKD2) and two PKD-like proteins (PKD2L1 and PKD2L2), the TRPML group containing three proteins related to the mucolipidosis Type IV protein (MCOLN1) and the TRPA group that -in mammals -so far only contains one member. A seventh group, the TRPN channels, have so far...

Dissociation of Regulated Trafficking of TRPC3 Channels to the Plasma Membrane from Their Activation by Phospholipase C

“…The mammalian transient receptor potential (TRP) 2 family of cation channel proteins consists of at least 28 members, which have been shown to mediate a wide range of diverse functions, including taste transduction, thermosensation, Ca 2ϩ and Mg 2ϩ absorption, and Ca 2ϩ entry (1)(2)(3). Mammalian TRPs have been further divided into three major subgroups as follows: the TRPV group, named after the founding member the vanilloid receptor; the TRPM group, named after the melastatin gene; and the TRPC or canonical TRP group, so named because these proteins share the greatest homology with the original Drosophila TRP.…”

“…Similarly to Drosophila TRP, the TRPC proteins, which consist of seven members (TRPC1-7), are activated downstream of phospholipase C (PLC) (4,5). PLC is activated as a result of stimulation of G-protein-coupled receptors or receptor protein-tyrosine kinases, and the enzyme is responsible for cleaving its substrate phosphatidylinositol 4,5-bisphosphate (PIP 2 ) into two second messenger molecules, inositol 1,4,5-trisphosphate (IP 3 ) and diacylglycerol (DAG) (6). IP 3 induces the release of Ca 2ϩ stored within the endoplasmic reticulum by interacting with and gating the IP 3 receptor, thus resulting in an increase in the cytoplasmic Ca 2ϩ concentration (7).…”

Pharmacological and functional properties of TRPM8 channels in prostate tumor cells

“…In this context, the ion channel TRPM8 has emerged as a promising new therapeutic target and biomarker of different stages of this disease [2,36,37]. The most important finding in our study is the discovery that TRPM8-mediated Ca 2+ responses, including kinetic properties and the sensitivity to drugs, are distinct in prostate cancer epithelial cells when compared to canonical responses of TRPM8 in transfected cells or in sensory neural tissue.…”

Unexpected Role of TRPC6 Channel in Familial Nephrotic Syndrome

“…The enthusiasm to develop specific TRPC6 antagonists must be balanced, however, by a few observations. Although the receptor-activated calcium transients may be dramatically enhanced in some TRPC6 mutants, the TRPC channels admit relatively small amounts of calcium per channel (94). In addition, because members of the TRPC3, 6, and 7 families share electrophysiologic characteristics, the gene products may serve some redundant roles (95).…”