Function and regulation of the TRPP3 channel

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Transient receptor potential polycystin-2L1 (TRPP3) is a member of the TRP superfamily of sensory ion channels. It was first reported in 1999 by us that TRPP3 acts as a cation channel activated by calcium. Since 2006 there has been increasing evidence that TRPP3 be a candidate acid sensor in the tongue, brain and retina, but its precise physiological roles have so far remained unclear. My PhD students JungWoo, Qian and MSc student Wang found in a paper in revision (J Biol Chem) that TRPP3 interacts with, and is functionally inhibited by a scaffolding protein called RACK1. Qian and my PhD student Carlos found (unpublished data) that TRPP3 interacts with acid sensing ion channels (ASICs) and glutamate receptors, suggesting its involvement in important cellular functions such as learning and memory. The OBJECTIVES are to study mechanisms underlying the calcium- and acid-induced TRPP3 channel activation, interaction of TRPP3 with ASICs, and implications of TRPP3 in learning and memory, through which HQP such as graduate and undergraduate students will be trained. HYPOTHESES: 1) that TRPP3 is activated by calcium-dependent phosphorylation of its N-terminus, 2) that TRPP3 and ASIC form an acid-sensitive channel complex on the surface membrane, and 3) that TRPP3 or TRPP3-ASIC complex is important for brain learning and memory. PROJECT #1, mechanisms underlying activation of TRPP3 by calcium and acid. PROJECT #2, physical and functional interaction of TRPP3 with ASICs. PROJECT #3, functional implications of TRPP3 or the TRPP3-ASIC interaction in learning and memory. My graduate and undergraduate students will perform experiments for the projects, using cellular and animal models combined with interdisciplinary approaches. SIGNIFICANCE. Through this program we will gain novel insights into molecular mechanisms underlying the calcium- and acid-induced TRPP3 channel activation, and how channel complex TRPP3-ASIC is implicated in pH-dependent learning and memory. This program together with other funded projects of Dr. Chen will provide excellent research topics and environments for training HQP.