It is becoming increasingly clear that susceptibility to many diseases results from a complex interaction between environmental factors and an individual's genetic make-up. We are interested in studying genetic variants of ion channels that could be associated with neuropathology. At the cellular level, ion channels and other plasma membrane proteins provide a first line of ‘interaction’ with extracellular ‘environmental’ factors such as ions and toxins. Ions are charged molecules that are crucial to life – required cofactors in vital cellular processes. Nevertheless, a delicate balance between environmental ions and cellular ions must be constantly maintained. Disruption of this delicate balance often leads to cellular distress. Ion channels regulate the influx and release of ions by providing a tightly controlled permeation pathway, usually available only when needed and specific for a particular ion. We are currently working on two ion channels, TRPM7 and TRPM2. Both belong to a newly discovered family of channels, the Transient Receptor Potential (TRP) family. TRPM7, a plasma membrane ion channel present in all cells, is believed to play a central role in regulating cellular homeostatic levels of Ca2+, Mg2+ and trace metals. We recently identified a TRPM7 variant in a subset of Guamanian amyotrophic lateral sclerosis and parkinsonism dementia complex (ALS/PDC) cases. The variant produces a protein with a missense mutation – threonine at position 1482 is replaced with isoleucine, T1482I. The hyperendemic ALS/PDC foci in the Western Pacific (including Guam) have been extensively studied over the years. Results of these studies suggest that a complex interaction between genetic predisposition and environmental factors are involved. Two candidate environmental triggers have been identified: altered mineral content in the environment and the cycad toxin, _-N-methylamino-L-alanine (L-BMAA). No viable genetic candidate has so far been identified. To our knowledge, T1482I is the first exon variant identified in Guamanian ALS/PDC. TRPM2 is closely related to TRPM7. It is highly expressed in the brain and in immune cells and has been shown to be activated by oxidative stress. We recently identified and characterized a genetic variant of TRPM2 in ALS/PDC. The variant, P1018L, affects calcium homeostasis in an expression system.

Publications and Abstracts

Meredith C. Hermosura, Hiroshi Takeuchi, Andrea Fleig, Andrew M. Riley, Barry V.L. Potter, Masato Hirata, and Reinhold Penner. (2000). InsP4 facilitates store-operated calcium influx by inhibition of InsP3 5-phosphatase. Nature. 408: 735-740.

Monica J. S. Nadler*, Meredith C. Hermosura*, Kazunori Inabe, Anne-Laure Perraud Qiqin Zhu, Tomohiro Kurosaki, Jean-Pierre Kinet, Reinhold Penner, Andrew M. Scharenberg, and Andrea Fleig. (2001). LTRPC7 is a MgATP-regulated divalent cation channel required for cellular viability. Nature. 411: 590-595. *equal contribution

Meredith C. Hermosura, Mahealani K. Monteilh-Zoller, Andrew Scharenberg, Reinhold Penner & Andrea Fleig. 2001. Dissociation of the store-operated calcium current ICRAC and the Mg2+-nucleotide-sensitive metal ion current MagNuM. J. Physiol. 539.2: pp. 445-458.

Yasuo Mori, Minoru Wakamori, Tomoya Miyakawa, Meredith C. Hermosura, Takaharu Okada, Yuji Hara, Mari Kurosaki, Emiko Mori,Kumiko Goto, Andrea Fleig, Reinhold Penner, Masamitsu Iino, and Tomohiro Kurosaki. 2002. Transient Receptor Potential 1 Regulates Capacitative Ca2+ Entry and Ca2+ Release from Endoplasmic Reticulum in B Lymphocytes. J. Exp. Med. 195: pp. 673-681.

Mahealani K. Monteilh-Zoller*, Meredith C. Hermosura*, Monica Nadler, Andrew Scharenberg, Reinhold Penner & Andrea Fleig. 2003. TRPM7 provides an ion channel mechanism for cellular entry of trace metal ions J. Gen.Physiol. 121: 49-60. *equal contribution

Meredith C. Hermosura, Hannah Nayakanti, Maxim V. Dorovkov, Fernanda R. Calderon, Alexey G. Ryazanov, David S. Haymer, and Ralph M. Garruto. (2005). A TRPM7 variant shows altered sensitivity to magnesium that may contribute to the pathogenesis of two Guamanian neurodegenerative disorders. Proc. Nat. Acad. Sci. 102: 11510-11515.

Meredith C. Hermosura and Ralph M. Garruto. 2007. TRPM7 and TRPM2 - Candidate Susceptibility Genes for Western Pacific ALS and PD? BBA – Molecular Basis of Disease, 1772: 822-835.

Meredith C. Hermosura, Aaron Cui, Ramon C.V. Go, Bennett Davenport, Cory M. Shetler, Justin W. Heizer, Carsten Schmitz, Gabor Mocz, Ralph M. Garruto and Anne-Laure Perraud. 2008. Altered functional properties of a TRPM2 variant in Guamanian ALS and PDC. Proc. Nat. Acad. Sci. 105: 18029-18034.

Recent Abstracts (2005-2008)

Brandie K. Reyes, Anna K. Yi, Aaron M. Cui, and Meredith C. Hermosura (2005). Preliminary investigation into the possible role of the TRPM2 channel in the etiology of diabetes. Presented at the 2nd Annual NIDDK Undergraduate Research Conference held August 4-5, 2005 in Honolulu, HI. Also presented at the Annual Biomedical Research Conference for Minority Students (ABRCMS) held November 2-5, 2005 in Atlanta, Georgia.

Ramon Christopher Go, Aaron M. Cui, Anna K. Yi, Cory M. Shetler and Meredith C. Hermosura (2006). Effects of extracellular and intracellular pH on the TRPM7 ion channel and its variant, T1482I. Won Best Over-All Presentation Award at the 2006 John A. Burns School of Medicine Biomedical Sciences Symposium, University of Hawaii.

Meredith C. Hermosura, Ramon C. Go, and Cory M. Shetler. (2006). Effects of the Cycad Toxin, L-BMAA, Oxidative Stress, and Low Calcium and Magnesium Levels on the TRPM7 Ion Channel and its T1482I Variant. Presented at the Specialized Neuroscience Research Program (SNRP) Annual Meeting in Fairbanks, Alaska, May 31-June 2, 2006.

Cory M. Shetler, Ramon C. Go, Aaron M. Cui, Anna K. Yi, Ralph M. Garruto, Gabor Mocz, and Meredith C. Hermosura. (2006). Identification and Functional Characterization of a Missense Mutant of the TRPM2 Ion Channel in Guamanian Amyotrophic Lateral Sclerosis and Parkinsonism Dementia. Ppresented at the Specialized Neuroscience Research Program (SNRP) Annual Meeting in Fairbanks, Alaska, May 31-June 2, 2006.

Ramon Christopher Go, Cory M. Shetler, Stuart H. Thompson, and Meredith C. Hermosura (2006). TRPM2 Provides a Pathway for Zinc Influx. Won the best oral presentation award (undergraduate category) at the NIH STEP-UP Summer Research Symposium held in Colorado State University on August 3-4, 2006.

Meredith C. Hermosura (2007). Oxidative stress hypothesis in the etiology of Western Pacific ALS and Parkinsonism Dementia – Is there TRPM2 and TRPM7 Involvement? Poster presented at the Gordon Research Conference on Oxidative Stress and Disease, Ventura, CA, March 11-16, 2007.

Meredith C. Hermosura, Ramon C. V. Go, Bennett Davenport, Cory M. Shetler, Aaron M. Cui, carsten Schmitz, Gabor Mocz, Ralph M. Garruto, and Anne-Laure Perraud (2007). Altered functional properties of a TRPM2 variant in Guamanian Amyotrophic Lateral Sclerosis and Parkinsonism Dementia. Societty for Neuroscience Annual Meeting, Nov. 3-6, 2007. San Diego, CA.

Meredith C. Hermosura (2008). Genetic variants of ion channels – susceptibility factors for complex diseases? Presented at the PBRC Symposium on Biodiversity, May 9, 2008. Honolulu, HI.