TRP channels as new pharmacological targets

Abstract

Changes in intracellular ion concentrations are universal triggers of cell activation. Ca, for instance, is one of the most versatile intracellular second messengers in eukaryotic cells involved in a wide range of cellular processes including exocytosis, contraction, cell proliferation, development and apoptosis. Stimulation of target cells with neurotransmitters, hormones or growth factors leads to an elevation of the intracellular Ca concentration brought about by release from intracellular stores and influx via Ca-permeable cation channels in the cell membrane (Clapham et al. 2001). While excitable cells like neurons are well equipped with voltage-gated ion channels mediating the bulk of cation influx, the molecular identity of cation entry channels in non-excitable cells has been completely mysterious for quite some time. A major leap forward in our understanding of agonist-triggered cation influx was achieved by the discovery of Drosophila melanogaster visual transduction channels associated with the transient receptor potential (trp) and the trp-like (trpl) mutant phenotypes. Since then a new mammalian gene family of TRP homologs has been identified by homology screening (Montell et al. 2002; Clapham et al. 2003). Based on structural homology and on systematic glycosylation scanning, TRP proteins are allocated to the structural superfamily of six-transmembrane spanning ion channels like voltage-gated K channels, the cyclic nucleotide-gated channel family, and single cassettes of voltage-activated Ca and Na channels (Fig. 1). Both Nand C-termini of TRP proteins are assumed to be localised intracellularly, and a channel pore loop appears to be bordered by transmembrane domains 5 and 6. In specialised cells, some members of the TRP family participate in sensory processes like vision and hearing as well as temperature, pain, gustatory and pheromone perception. In addition, many TRP proteins are involved in ubiquitous, very basic cellular processes like sensing of osmotic or oxidative stress and mediating agonist-induced cation entry (Clapham 2003). Based on primary amino acid homology, the conventional TRP proteins can be classified into three subfamilies: TRPC, TRPV, and TRPM (see Fig. 1). Three additional, more distantly related subfamilies have recently been defined: ANKTM1, a Ca-permeant, non-selective cation channel, is the only mammalian member of the TRPA branch of TRP proteins. It is activated by noxious cold temperature, pungent mustard oil compounds and may additionally serve as a mechanosensitive transduction channel in auditory hair cells as well as an ionotropic cannabinoid receptor. The three mucolipins, TRPML1, 2, and 3, appear to be ion channels in intracellular vesicles. Mutations in TRPML1 cause mucolipidosis type IV, a neurodegenerative lysosomal storage disorder, while genetic defects in TRPP2, a member of the TRPP subfamily, are frequently encountered in patients suffering from autosomal dominant polycystic kidney disease. The current compilation of review articles covers salient features of TRPC, TRPV, TRPM, and TRPP proteins at the cutting edge of science. In particular, the authors continue to explore the pharmacotherapeutic potential of this new class of ion channels, a fruitful endeavor that was started at the 25th Symposium at Rauischholzhausen Castle on “TRP channels as Pharmacological Targets” which took place on June 10–12, 2004. TRPC proteins all share a common gating mechanism that involves the activation of phospholipase C isoforms and thus constitute prime molecular candidates responsible for phospholipase C-dependent cation influx. The molecThis revised version was published online in June 2005 with corrections to the Reference list