The A2A adenosine receptor (A2A-R) is a major target of caffeine, the most widely used psychoactive substance in the world. It is a G protein-coupled receptor. Stimulation of the A2A-R leads to activation of protein kinase A and protein kinase C. Besides the classical signal transduction pathways, novel interacting proteins (e.g., TRAX) of the A2A-R have been shown to contribute to the action of A2A-R. We and others have demonstrated that A2A-R stimulation offers protection against Huntington’s disease and ischemia-reperfusion injury of several peripheral tissues. Due to the functional importance of the A2A-R, we are actively investigating the regulation and signal transduction of the A2A-R in vivo. Specifically, we will (1) develop treatments for Huntington’s disease based on the functions and pharmacological properties of the A2A-R, (2) characterize the composition and the functional relevance of the “A2A-R signalosome” under physiological and pathological conditions, and (3) investigate the transcriptional and post-transcriptional regulation of the A2A-R under physiological and pathological conditions. The principal objective of this research group is to understand the molecular mechanisms underlying the physiological functions of A2A-R and to establish potential therapeutic treatments for HD.
Chern, Y, Chiou J-Y, Lai H-L and Tsai M-H. (1995) Regulation of Adenylyl Cyclase Type VI Activity During Desensitization of the A2A-Adenosine Receptor-Mediated cAMP Response:A Role for Protein Phosphatase 2A. Mol.Pharmacology, 48:1-8.
Chu Y-Y, Tu K-H, Lee Y-C, Kuo Z-J, Lai H-L and Chern Y. (1996) Characterization of Rat A2A Adenosine Receptor Gene. DNA and Cell Biology, 15: 329-337.
Lai H-L, Yang T-H, Messing RO, Ching Y-H, Lin S-C and Chern Y. (1997) Protein kinase C Inhibits Adenylyl Cyclase Type VI Activity During Desensitization of the A2A-Adenosine Receptor-Mediated cAMP Response. J. Biol.Chem. 272: 4970-4977.
Chang YH, Conti M, Lee Y-C, Lai H-L, ChingY-H and Chern Y. (1997) Activation of Phosphodiesterase IV During Desensitization of the A2A-adenosine Receptor-mediated cAMP Response in Rat Pheochromocytoma (PC12) Cells. J. Neurochem. 69: 1300-1309.
Liu F-C, Wu G-C, Hsieh S-T, Lai H-L, Wang H-F, Wang T-W and Chern Y. (1998) Expression of Type VI Adenylyl Cyclase in the Central Nervous System: Implication for a potential regulator of multiple signals in different neurotransmitter systems. FEBS Lett.436:92-98.
Lai H-L, Lin T-H, Kao Y-Y, Lin W-J, Hwang M-J and Chern Y. (1999) The Nterminal domain of Type VI Adenylyl Cyclase Mediates Its Inhibition by Protein Kinase C. Mol. Pharm. 56: 644-650.
Lee Y-C, Chang C-W, Su C-W, Lin T-N, Sun SH, Lai H-L and Chern Y. (1999) The 5' Untranslated Regions of Rat A2A Adenosine Receptor Gene Function as Negative Translational Regulators. J. Neurochem. 73: 1790-1798.
Lin T-H, Lai H-L, Kao Y-Y, Sun C-N, Hwang M-J and Chern Y. (2002) Protein kinase C inhibits type VI adenylyl cyclase (ACVI) by phosphorylating the regulatory N domain and two catalytic C1 and C2 domains. J. Biol. Chem. 277: 15721-15728.
Cheng H-C, Shih H-M, and Chern Y. (2002) Essential role of CREB activation by A2A adenosine receptors in rescuing the NGF-induced neurite outgrowth impaired by blockage of the MAPK cascade. J. Biol. Chem. 277: 33930- 33942.
Lee Y-C, Lai H-L, Sun C-N, Chien C-L, and Chern Y. (2003) Identification of nuclear factor 1 (NF1) as a transcriptional modulator of rat A2A adenosine receptor. Mol Brain Res 111: 61-73.
Huang C-L, Huang N-K, Shyue S-K, and Chern Y. (2003) H2O2 induces loss of dopamine transporter activity: a calcium-dependent oxidative mechanism. J. Neurochem. 86: 1247-1259.
Lee Y-C, Chien C-L, Sun C-N, MC Chiang, Huang C-L, Huang N-K, Lai H-L, Lin Y-S, Chiou S-Y, Liao W-L, Liu F-C, Wang L, Tai M-H, Lin T-N and Chern Y. (2003) Characterization of the rat A2A adenosine receptor gene: a 4.8-kb promoter-proximal DNA fragment confers selective expression in the central nervous system. Eur. J. Neurosci. 18: 1786- 1796.
Kao Y-Y, Lai H-L, Hwang M-J, and Chern Y (2004) An Important functional role of the N terminus domain of type VI adenylyl cyclase (ACVI) in Giα-mediated inhibition. J. Biol. Chem. 279: 34440 – 34448.
Chou J-l, Huang C-L, Lai H-L, Hong A. C., Chien C-L, Kao Y-Y and Chern Y. (2004) Regulation of type VI adenylyl cyclase by Snapin, a SNAP25 interacting protein. J. Biol. Chem. 279: 46271-46279.
Chou S-Y, Lee Y-C, Chen H-M, Chiang M-C, Lai H-L, Chang H-H, Wu-Y-C, Sun C-N, Chien C-L, Lin Y-S, Wang S-C, Tung Y-Y, Chang C and Chern Y. (2005) CGS21680 attenuates symptoms of Huntington’s disease in a transgenic mouse model. J. Neurochem. 93: 310-320.
Chiang M-C, Lee Y-C, Huang C-L and Chern Y. (2005) CREB contributes to suppression of the A2A adenosine receptor promoter by mutant Huntingtin with expanded polyglutamine resides. J. Biol. Chem. 280: 14331–14340.
Sun C-N, Cheng H-C, Chou J-l, , Lee S-Y, Lin Y-W, Lai H.-L. Chen H-M and Chern Y. (2006) Rescue of p53 blockage by the A2A adenosine receptor via a novel interacting protein, Translin-associated protein X. Mol. Pharmacology. 70:454-466.
Chiang M-C, Chen H-M, Lee Y-H, Chang H-H, Wu-YC, Soong B-w, Chen C-M, Wu Y-R, Wu J-Y, Liu C-S, Niu D-M, Chen Y-T, and Chern Y. (2007) Dysregulation of C/EBPα by mutant Huntingtin with expanded polyglutamine residues contributes to the urea cycle deficiency in Huntington’s disease. Human Molecular Genetics, 16: 483- 498.
Chiang M-C, Juo C-G, Chang H-H, Chen H-M, Yi EC and Chern Y. (2007) Systematic uncovering of multiple pathways underlying the pathology of Huntington’s disease by an acid-cleavable isotope-coded affinity taq approach. Mol. Cell. Proteomics, 6: 781 – 797.
Huang NK, Chern Y, Fang JM, Lin CI, Chen WP, and Lin YL. (2007) Neuroprotective principles from Gastrodia elata. J Nat Prod. 70: 571-574.
Wang S-C, Lai H-L, Chiou Y-T, Ou R-K, Chuen-lin Huang, and Chern Y (2007). Regulation of type V adenylyl cyclase by Ric8a, a guanine nucleotide exchange factor. Biochem. J. 406: 383-388.
Fredholm BB, Chern Y, Franco R and Sitkovsky M (2007). Aspects of the general biology of adenosine A2A signaling. Progress in Neurobiology 83: 263-276.
