Összes szerző

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Tóth Ádám V.

az alábbi absztraktok szerzői között szerepel:

Tóth Ádám Viktor
Molecular characterization of pathological and tissue-specific TRPM2 cation channel variants

Aug 30 - szerda

15:30 – 17:00

II. Poszterszekció

P57

Molecular characterization of pathological and tissue-specific TRPM2 cation channel variants

Ádám V. Tóth¹, Ádám Bartók¹ and László Csanády¹

¹ Department of Biochemistry, Semmelweis University, Budapest, Hungary

TRPM2 is a temperature-sensitive, Ca2+-permeable, non-selective cation channel, showing high level of expression in cells of the central nervous system, bone marrow, granulocytes and pancreatic β-cells. Activation of the channel requires the simultaneous intracellular presence of adenosine diphosphate ribose (ADPR), Ca2+ ions and phosphatidylinositol 4,5-bisphosphate (PIP2). In these cells, TRPM2 contributes to Ca2+ influx resulting in important physiological and pathological functions, such as body temperature regulation, cytokine production, oxidative stress response, inflammation or controlled cell death. Moreover, certain TRPM2 point mutations show close genetic connection with bipolar disorder (D543E, R755C) [1] or amyotrophic lateral sclerosis and Parkinson's dementia (P1018L) [2]. Interestingly, alternative splice products were isolated from healthy neutrophil granulocytes (ΔC-TRPM2) [3] and from striatum (SSF-TRPM2) [4], which presumably modify the ligand specificity and function of the channel in a cell-specific manner.

Until now, the mentioned variants have only been investigated using fluorescent imaging techniques or whole-cell electrophysiological methods providing limited opportunities to study the ligands acting intracellularly. Our aim is to examine the listed ion channel variants in molecular details. To this end, expression vector encoding TRPM2 variants have been produced and expressed transiently in HEK cells. Functional measurements are performed by inside-out patch clamp configuration enabling reliable recordings of micro- and macroscopic currents and fast exchange of intracellular ligands. With our method, it is possible to map crucial biological and biophysical parameters of the channel variants: ADPR and Ca2+ sensitivity, gating parameters, inactivation kinetics, temperature dependence. This detailed knowledge is essential for a comprehensive understanding of the role of these mutants in pathomechanisms and tissue-specific variant functions.

References

[1] A. McQuillin et al. Mol Psychiatry 11, 134-142 (2006)

[2] M. C. Hermosura et al. Proc Natl Acad Sci USA 105, 18029-34 (2008)

[3] E. Wehage et al. J Biol Chem 277, 23150-6 (2002)

[4] T. Uemura et al. Biochem Biophys Res Commun 328, 1232-43 (2005)