Adenosine research

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Adenosine and its receptors, pathophysiological significance and therapeutic opportunities.

The focus of our research is on adenosine receptors and on the actions of the most widely used of all psychoactive drugs, caffeine, which acts as an inhibitor at these receptors. There are four cloned forms of adenosine receptors and their pharmacological characteristics have been examined using CHO cells that express the human A1, A2A, A2B and A3 receptors. The signaling properties of the receptors are studied in the same cells, but also in several types of cells where they are naturally expressed.

By in situ hybridization, immunocytochemistry and receptor autoradiography the distribution of the receptors in tissues and cells is studied. In particular we have examined their ontogeny and how the local expression of the receptors is altered by long, or short-term drug treatment or physiological changes.

The natural ligand, adenosine, is a modulator rather than a transmitter or a hormone, and it is therefore important to examine how the adenosine receptors influence signaling mediated via other receptors. Considerable effort is spent on elucidating the interactions between co expressed A2A and dopamine D2 receptors, because this interaction is a key to the central actions of caffeine. In recent years our efforts have been concentrated on elucidating the pathophysiological roles of adenosine using receptor knockouts. Most recently the roles of adenosine receptors in the regulation of immune competent cells in the CNS and in the central regulation of metabolism have been of special interest.

Group members

Past members include the graduate students listed below and several postdoctoral fellows and senior research colleagues:

Sixtus Hynie
Tom Dunwiddie
Felicita Pedatata
Ewa Kontny
Fiona Parkinson
Anthony Balmforth
Gary DeLander
Rodrigo Cunha
Vijay Urmalia
Mervin Maze
Harry Robertson

Projects

There are no ongoing experimental projects in the group. Current research is in collaboration with other laboratories at the department and abroad.

Financial support

No major grants. 

Collaborations

At the Department pf Physiology and Pharmacology: Gunnar Schulte; Mattias Carlström; Marie Björnholm

In Sweden: A Erik G Persson; Gunnar Nilsson; Ulrika Ådén; JiangNing Yang; Ola Winqvist

Abroad: Jiang-Fan Chen (Boston); Susan Masino (Boston); Holger Eltzschig (Denver); Jana Sawynok (Halifax); Rodrigo Cunha (Coimbra); Ping-Sheng Hu (Shanghai); Cristina Limatola (Rom).

Publications

A total of about 750 publications cited more than 31 000 times. Representative papers are:

Effects of adenosine on adrenergic neurotransmission; prejunctional inhibition and postjunctional enhancement.
Hedqvist P, Fredholm BB.
NAUNYN-SCHMIEDEBERGS ARCHIVES OF PHARMACOLOGY  Volume: 293   Issue: 3   Pages: 217-223   DOI: 10.1007/BF00507344   Published: 1976. Cited: 312 times

Purine levels in the intact rat brain. Studies with an implanted perfused hollow fibre.
Zetterström T, Vernet L, Ungerstedt U, Tossman U, Jonzon B, Fredholm BB.
NEUROSCIENCE LETTERS  Volume: 29   Issue: 2   Pages: 111-115   DOI: 10.1016/0304-3940(82)90338-X   Published: 1982. Cited: 321 times

ATP and its metabolite adenosine act synergistically to mobilize intracellular calcium via the formation of inositol 1,4,5-trisphosphate in a smooth muscle cell line. 
Gerwins P, Fredholm BB.
JOURNAL OF BIOLOGICAL CHEMISTRY  Volume: 267   Issue: 23   Pages: 16081-16087   Published: 1992. Cited: 109 times

Antagonism of adenosine A2A receptors underlies the behavioural activating effect of caffeine and is associated with reduced expression of messenger RNA for NGFI-A and NGFI-B in caudate-putamen and nucleus accumbens.
Svenningsson P, Nomikos GG, Ongini E, Fredholm BB.
NEUROSCIENCE  Volume: 79   Issue: 3   Pages: 753-764   DOI: 10.1016/S0306-4522(97)00046-8   Published: 1997. Cited: 111 times

Actions of caffeine in the brain with special reference to factors that contribute to its widespread use.
Fredholm BB, Bättig K, Holmén J, Nehlig A, Zvartau EE.
PHARMACOLOGICAL REVIEWS  Volume: 51   Issue: 1   Pages: 83-133   Published: 1999. Cited: 869 times

Hyperalgesia, anxiety, and decreased hypoxic neuroprotection in mice lacking the adenosine A(1) receptor.  
Johansson B, Halldner L, Dunwiddie TV, et al. 
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA  Volume: 98   Issue: 16   Pages: 9407-9412   DOI: 10.1073/pnas.161292398   Published: 2001. Cited: 265 times

Comparison of the potency of adenosine as an agonist at human adenosine receptors expressed in Chinese hamster ovary cells.  
Fredholm BB, Irenius E, Kull B, Schulte G.
BIOCHEMICAL PHARMACOLOGY  Volume: 61   Issue: 4   Pages: 443-448   DOI: 10.1016/S0006-2952(00)00570-0   Published: 2001. Cited: 170 times

Adenosine A2(A), but not A(1), receptors mediate the arousal effect of caffeine.  
Huang ZL, Qu WM, Eguchi N, Chen JF, et al. 
NATURE NEUROSCIENCE  Volume: 8   Issue: 7   Pages: 858-859   DOI: 10.1038/nn1491   Published: 2005. Cited: 205 times 

Adenosine, an endogenous distress signal, modulates tissue damage and repair.  
Fredholm BB.
CELL DEATH AND DIFFERENTIATION  Volume: 14   Issue: 7   Pages: 1315-1323   DOI: 10.1038/sj.cdd.4402132   Published: 2007. Cited: 229 times

Adenosine receptors as drug targets - what are the challenges? 
Chen JF, Eltzschig HK, Fredholm BB.
NATURE REVIEWS DRUG DISCOVERY  Volume: 12   Issue: 4   Pages: 265-286   DOI: 10.1038/nrd3955   Published: 2013. Cited: 10 times

Dissertations

Bertil B. Fredholm (1970)
Paul Hjemdahl (1976)
Erik Belfrage (1978)
Jan Wager (1980)
Lars Gustafsson (1980) 
Alf Sollevi (1981)
Göran Jurell (1981) 
Bror Jonzon (1984)
Thomas Kahan (1985) 
Johan Fastbom (1988)
Maria Ransjö (1988)
Olof Larsson (1989) 
Janet Ng (1989) 
Gabriel von Euler (1989)
Marianne Dunér Engström (1990)
Christer Nordstedt (1990)
Ping-Sheng Hu (1991)
Ingeborg van der Ploeg (1992)
Anders Kvanta (1992)
Pär Gerwins (1994)
Nedret Altiok (1995)
Björn Johansson (1996)
Shao-Yu Jin (1997)
Per Svenningsson (1999)
Björn Kull (2000)
Giulia Arslan (2000)
Ulrika Ådén (2001)
Gunnar Schulte (2003)
Linda Halldner (2003)
Stina Johansson (2007) 
Olga Björklund (2008)
Kim Dekermendjian (2008)
Ricard Nergårdh (2008)
Jiangning Yang (2008)

Contact us

Associated

Bertil Fredholm

Organizational unit: Department of Physiology and Pharmacology (FYFA), C3
E-mail: Bertil.Fredholm@ki.se

Pharmacology