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J. Biol. Chem., Vol. 280, Issue 23, 22540-22548, June 10, 2005

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Alternative Splicing Switches the Divalent Cation Selectivity of TRPM3 Channels^*

Johannes Oberwinkler, Annette Lis, Klaus M. Giehl, Veit Flockerzi, and Stephan E. Philipp¶

From the Institut für Experimentelle und Klinische Pharmakologie und Toxikologie and Anatomisches Institut, Universität des Saarlandes, D-66421, Homburg, Germany

TRPM3 is a poorly understood member of the large family of transient receptor potential (TRP) ion channels. Here we describe five novel splice variants of TRPM3, TRPM31–5. These variants are characterized by a previously unknown amino terminus of 61 residues. The differences between the five variants arise through splice events at three different sites. One of these splice sites might be located in the pore region of the channel as indicated by sequence alignment with other, better-characterized TRP channels. We selected two splice variants, TRPM31 and TRPM32, that differ only in this presumed pore region and analyzed their biophysical characteristics after heterologous expression in human embryonic kidney 293 cells. TRPM31 as well as TRPM32 induced a novel, outwardly rectifying cationic conductance that was tightly regulated by intracellular Mg²⁺. However, these two variants are highly different in their ionic selectivity. Whereas TRPM31-encoded channels are poorly permeable for divalent cations, TRPM32-encoded channels are well permeated by Ca²⁺ and Mg²⁺. Additionally, we found that currents through TRPM32 are blocked by extracellular monovalent cations, whereas currents through TRPM31 are not. These differences unambiguously show that TRPM3 proteins constitute a pore-forming channel subunit and localize the position of the ion-conducting pore within the TRPM3 protein. Although the ionic selectivity of ion channels has traditionally been regarded as rather constant for a given channel-encoding gene, our results show that alternative splicing can be a mechanism to produce channels with very different selectivity profiles.

Received for publication, March 21, 2005 , and in revised form, April 8, 2005.

The nucleotide sequence(s) reported in this paper has been submitted to the DDBJ/GenBank^TM/EBI Data Bank with accession number(s) AJ544532, AJ544534, AJ544533, AJ544535, and AJ544536.

^* This work was supported by grants from the Deutsche Forschungsgemeinschaft (Emmy-Noether Programm (to J. O.), SFB 530 (to S. E. P.)) and from the Universität des Saarlandes (HOMFOR). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement"in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^¶ To whom correspondence should be addressed: Experimentelle und Klinische Pharmakologie und Toxikologie, Gebäude 46, Universität des Saarlandes, 66421 Homburg, Germany. Tel.: 49-6841-1626152; Fax: 49-6841-1626402; E-mail: stephan.philipp{at}uniklinik-saarland.de.

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