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TRPM2 is a member of the transient receptor potential melastatin-related (TRPM) family of cation channels, which possesses both ion channel and ADP-ribose hydrolase functions. TRPM2 has been shown to gate in response to oxidative and nitrosative stresses, but the mechanism through which TRPM2 gating is induced by these types of stimuli is not clear. Here we show through structure-guided mutagenesis that TRPM2 gating by ADP-ribose and both oxidative and nitrosative stresses requires an intact ADP-ribose binding cleft in the Cterminal nudix domain. We also show that oxidative/ nitrosative stress-induced gating can be inhibited by pharmacological reagents predicted to inhibit NAD hydrolysis to ADP-ribose and by suppression of ADP-ribose accumulation by cytosolic or mitochondrial overexpression of an enzyme that specifically hydrolyzes ADP-ribose. Overall, our data are most consistent with a model of oxidative and nitrosative stress-induced TRPM2 activation in which mitochondria are induced to produce free ADP-ribose and release it to the cytosol, where its subsequent accumulation induces TRPM2 gating via interaction within a binding cleft in the C-terminal NUDT9-H domain of TRPM2.Eukaryotic cells have been shown to react and adapt to conditions of oxidative stress produced by disulfide-inducing chemicals, reactive oxygen species (ROS), 1 or reactive nitrogen species (RNS) through a variety of redox-sensitive signaling pathways (variously reviewed in Refs. 1-12). Recently, the TRPM2 cation channel has been shown to undergo gating in response to oxidative or nitrosative stress occurring upon ROS or RNS exposure (13,14). As TRPM2 is a novel dual function protein that possesses both ion channel and ADP-ribose hydrolase functions (15, 16), there has been great interest in understanding the molecular mechanisms through which oxidative and nitrosative stress activate TRPM2 channels, as well as the physiological role(s) of TRPM2-mediated ion fluxes and enzymatic activity in the context of cellular exposure to ROS and RNS.TRPM2 is classified as a member of the transient receptor potential melastatin-related (TRPM) ion channel family based on the homology of its Ϸ600 amino acid N-terminal domain and Ϸ300 amino acid channel-forming domain to corresponding regions of other TRPM family members. The enzymatic function of TRPM is encoded by a C-terminal domain, designated the NUDT9-homology (NUDT9-H) domain, which is homologous to the NUDT9 ADP-ribose hydrolase (15,17). In vitro studies of TRPM2 channel function using patch clamp techniques have suggested that ADP-ribose and NAD are both able to directly induce gating of full-length TRPM2 channels (14,15,18), and in vitro studies of the NUDT9-H domain demonstrate that it has a low level of ADP-ribose hydrolase activity and the apparent capacity to interact with NAD through its nudix hydrolase enzymatic motif (14, 15). However, there is a significant gap in understanding how the in vitro data on TRPM2 function relate to oxidative/nitrosative stress-induced TRPM2 gating in intact c...

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Let C 0 g be the category of finite-dimensional integrable modules over the quantum affine algebra U ′ q (g) and let R A∞ -gmod denote the category of finitedimensional graded modules over the quiver Hecke algebra of type A ∞ . In this paper, we investigate the relationship between the categories C 02010 Mathematics Subject Classification. 81R50, 16G, 16T25,17B37.

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In this paper, we prove Khovanov-Lauda's cyclotomic categorification conjecture for all symmetrizable Kac-Moody algebras. Let U q (g) be the quantum group associated with a symmetrizable Cartan datum and let V (Λ) be the irreducible highest weight U q (g)-module with a dominant integral highest weight Λ. We prove that the cyclotomic Khovanov-Lauda-Rouquier algebra R Λ gives a categorification of V (Λ).2000 Mathematics Subject Classification. 05E10, 16G99, 81R10.This paper is organized as follows. In Section 2 and Section 3, we recall basic properties of quantum groups, integrable highest weight modules and the Khovanov-Lauda-Rouquier algebra R. In Section 4, we investigate the structure of cyclotomic Khovanov-Lauda-Rouquier algebra R Λ and prove the exact sequence (1.2), and then show that the functors E Λ i , F Λ i (i ∈ I) are exact and send projectives to projectives. Section 5 is devoted to the sl 2 -categorification theory. In Section 6, we finish the proof of Khovanov-Lauda's cyclotomic categorification conjecture.

We present a uniform construction of level 1 perfect crystals B for all affine Lie algebras. We also introduce the notion of a crystal algebra and give an explicit description of its multiplication. This allows us to determine the energy function on B ⊗ B completely and thereby give a path realization of the basic representations at q = 0 in the homogeneous picture.