Adenosine production by cells is increased when cellular energy utilization and the breakdown of adenosine tri-phosphate (ATP) is increased. Thus, adenosine levels are elevated in tissues when there is not enough oxygen in the cells or during other pathological processes involving cellular stress, inflammation, and tissue injury. Through interaction with four related receptors termed A1, A2A, A2B, and A3 adenosine receptors - proteins found on the surface of cells that recognize adenosine and related ligands - adenosine affects many different disease processes, ranging from ischemic heart disease to cancer.
We are investigating the biological function of the two least understood adenosine receptor subtypes, the A2B and A3 adenosine receptors. In particular, the team is investigating how the A3 adenosine receptor modulates activity of certain immune cells and helps to protect the heart from ischemia/reperfusion injury, known commonly as a heart attack. As part of this project, new ligands for the A3 adenosine receptor are being developed, including novel allosteric modulator compounds that enhance the ability of the receptor to be activated by binding to a region that is distinctly different than the binding site for adenosine. In a second project, we are investigating the novel hypothesis that the A2B adenosine receptor contributes to stiffening of the heart during certain chronic cardiovascular diseases that lead to heart failure by promoting the formation of excess connective tissue, a pathological process termed cardiac fibrosis. A basic understanding of the function of each of the adenosine receptors is anticipated to identify new approaches for the treatment of a wide range of diseases.
Ntantie E, Gonyo P, Lorimer E, McAllister D, Kalyanaraman B, Dwinell M, Auchampach JA, Williams CL (2013). Identification of an adenosine-mediated signaling pathway that suppresses prenylation of the small GTPase Rap1B and promotes cell scattering. Science Signaling 6:ra39.
Kozma E, Gizewski ET, Tosh DK, Auchampach JA, Jacobson KA (2013). Characterization of fluorescent, selective agonist probes of the A3 adenosine receptor by flow cytometry. Biochemical Pharmacology 85:1171-1181.
Chandrasekera PC, Wan TC, Gizewski ET, Auchampach JA, Lasley RD (2013). Adenosine A1 receptors heterodimerize with b1- and b2-adrenergic receptors creating novel receptor complexes with altered G protein coupling and signaling. Cellular Signaling 25:736-742.
Tosh D, Deflorian F, Phan K, Gao ZG, Wan TC, Gizewski ET, Auchampach JA, Jacobson KA (2012). Structure-guided design of A3 adenosine receptor-selective nucleosides: Combination of 2-arylethynyl and Bicyclo[3.1.0]hexane substitutions. Journal of Medicinal Chemistry 55:4847-4860.
Fisher JB, Kim MS, Ge ZD, Wan TC, Christian D, Twarosk7i K, Auchampach JA, Lough J (2012). Stress-induced cell-cycle activation in Tip60 haploinsufficient adult cardiomyocytes. PLOS ONE 7(2): e31569.
Du L, Nithipatikom K, IJzerman AP, van Veldhoven JPD, Jacobson KA, Gross GJ, Auchampach JA (2012). Protection from myocardial ischemia/reperfusion injury by a positive allosteric modulator of the A3 adenosine receptor. Journal of Pharmacology and Experimental Therapeutics 340:210-217.
Wan TC, Tosh DK, Du L, Gizewski ET, Jacobson KA, Auchampach JA (2011). Polyaminoamine (PAMAM) dendrimer conjugate specifically activates the A3 adenosine receptor to improve post-ischemic/reperfusion function in isolated mouse hearts. BMC Pharmacology 11:11 (1-12).
van der Hoeven D, Gizewski E, Wan TC, Auchampach JA (2011). A role for the low-affinity A2B adenosine receptor in suppressing superoxide production by neutrophils. Journal of Pharmacology and Experimental Therapeutics 338:1004-1012.
Xiang, S, Ge ZD, Wan TC, Auchampach JA, Gross GJ, Duan D. (2011). Characterization of a critical role of CFTR chloride channels in cardioprotection against ischemia/reperfusion injury. Acta Pharmacologica Sinica 32:824-833.
Maas JE, Wan TC, Figler RA, Gross GJ, Auchampach JA (2010). Evidence that the acute phase of ischemic preconditioning does not require signaling by the A2B adenosine receptor. Journal of Molecular and Cellular Cardiology 49:886-893.
van der Hoeven D, Gizewski E, Hoshino M, Auchampach JA (2010). Activation of the A3 adenosine receptor inhibits fMLP-induced Rac activation in mouse bone marrow neutrophils. Biochemical Pharmacology 79:1667-1673.
Auchampach JA, Gizewski ET, Wan TC, de Castro S, Brown GG, Jacobson KA (2010). Synthesis and pharmacological characterization of [125I]MRS5127, a high affinity selective agonist radioligand for the A3 adenosine receptor. Biochemical Pharmacology 79:967-973.
Ge ZD, van der Hoeven D, Maas JE, Wan TC, Auchampach JA (2010). A3 adenosine receptor activation during reperfusion reduces infarct size through actions on bone marrow-derived cells. Journal of Molecular and Cellular Cardiology 49:280-286.
Kreckler LM, Wan TC, Gizewski E, Auchampach JA (2009). Adenosine suppresses LPS-induced TNF-α production from murine macrophages by inhibiting gene transcription through a PKA- and EPAC-independent signaling pathway. Journal of Pharmacology and Experimental Therapeutics 331:1051-1061.
Auchampach JA, Kreckler LM, Wan TC, Maas JE, van der Hoeven D, Gizewski E, Narayanan J, Maas GE. (2009). Pharmacological characterization of A2B adenosine receptors from mouse, rabbit, and dog. Journal of Pharmacology and Experimental Therapeutics 329:2-13.
van der Hoeven D, Wan TC, and Auchampach JA (2008). Activation of A3 adenosine receptors in mouse bone marrow neutrophils inhibits superoxide production and chemotaxis. Molecular Pharmacology 74:685-696.
Melman A, Gao ZG, Kumar D, Wan TC, Gizewski E, Auchampach JA, Jacobson KA. (2008) Design of (N)-methanocarba adenosine 5’-uronamides as species-independent A3 receptor-selective agonists. Bioorganic Medicinal Chemistry Letters 18:2813-2819.
Wan TC, Ge ZD, Bienengraeber MW, Tampo A, Kwok WM, Tracey WR, Gross GJ, Auchampach JA (2008). The A3 adenosine receptor agonist CP-532,903 protects against myocardial ischemia/reperfusion injury via the sarcolemmal ATP sensitive potassium channel. Journal of Pharmacology and Experimental Therapeutics 324:234-243.
Ge ZD, Peart JN, Kreckler LM, Wan TC, van der Hoeven D, Gross GJ, Jacobson MA, Auchampach JA (2006). Cl-IB-MECA [2-chloro-N6-(3-iodobenzyl)adenosine-5’-N-methycarboxamide] reduces ischemia/reperfusion injury in mice by activating the A3 adenosine receptor. Journal of Pharmacology and Experimental Therapeutics 319:1200-1210.
Nelson TJ, Ge ZD, Van Orman J, Barron M, Rudy-Reil D, Hacker TM, Misra R, Duncan SA, Auchampach JA, Lough J. (2006). Improved cardiac function in infarcted mice after treatment with pluripotent embryonic stem cells. Anatomical Record 288A:1216-1224.
Carrier E, Auchampach JA, Hillard CJ (2006). Inhibition of the equilibrative nucleoside transporter by cannabidiol: A novel mechanism of cannabinoid immunosuppression. Proceedings of the National Academy of Sciences USA 103:7895-7900.
Kreckler LM, Wan TC, Ge ZD, Auchampach JA (2006). Adenosine inhibits TNF-a release from mouse peritoneal macrophages via A2A and A2B, but not A3 adenosine receptors. Journal of Pharmacology and Experimental Therapeutics 317:172-180.