TRPM channels form a subfamily of the Transient Receptor Potential superfamily of non-selective cation channels. The TRPM family members share ~30-65% amino acid identity over the entire protein sequence (GAP alignment) – this identity increases in the ion channel domain. TRPM members 2, 6 and 7 consist of a TRP channel linked to a C-terminal enzymatic domain. TRPM2 includes a C-terminal ADP-ribose pyrophosphatase domain and has been shown to be gated by ADP-ribose and H₂O. TRPM2 is highly expressed in the brain and activation of TRPM2 by H₂Oin recombinant systems results in cell damage or death. Levels of ADPR increase during metabolic and oxidative stresses which occurr in neurodegenerative conditions such as Alzheimer′s Disease, Parkinson′s Disease and Multiple Sclerosis.We have cloned human, rat and mouse TRPM2 and 5 paralogues of TRPM2 (members 3, 4, 6, 7 and 8). Extensive splice variation was observed in cDNA clones of these channels. Bioinformatics analysis of the TRPM proteins has predicted the protein topology and regions of functional significance (Perraud et al., 2003) and a protein alignment of the TRPM channels has identified regions that are highly conserved between TRPM members. The level of homology over these regions might indicate their importance for channel function. We have frequently observed a truncated isoform consisting only of the N-terminal region of the protein. Short isoforms of TRPM4 and TRPM7 have been isolated which, like short TRPM1 (Xu et al., 2001), do not contain any transmembrane domains. A short variant of mouse TRPM2 was identified which translates to a protein that includes putative transmembranes 1 and 2 and is highly similar to a short human TRPM2. Both human TRPM1-short and TRPM2-short (see oral presentation by E. Fonfria et al., GSK) have been shown to behave as dominant negative variants albeit by different mechanisms. Interactions between the N-terminal domains of the Drosophila TRP proteins have been reported in the assembly of functional TRP channels (Xu et al., 1997 and Xu et al., 2000). If TRPM proteins interact through the N-terminus, this raises the possibility that variations in the N-terminus affect the ability of TRPM channels to form homo- or hetero-multimers and hence affect the physiological characteristics of the multimer channel. We have identified and cloned at least 2 alternative exon 1 transcripts of rat TRPM3 which translate to proteins that differ only in the length of the N-terminal region.We discuss the possible effects of the observed deletions or insertions found in 7 TRPM genes (incl. a novel rat TRPM3) on channel function.