According to Essential Science
Indicators fromThomson
Reuters, the most-cited paper in the field
of Pharmacology & Toxicology for the period of
January 1, 1998 to August 31, 2008 is "Receptors for
purines and pyrimidines," (Pharmacol. Rev.
50[3]: 413-92, September 1998), by Dr. Vera Ralevic and
Professor Geoffrey Burnstock. This paper currently has
1,968 cites.
Dr. Ralevic is an Associate Professor and Reader in the School of
Biomedical Sciences at the University of Nottingham. Professor Burnstock is
the President of the Autonomic Neuroscience Centre at Royal Free and
University College Medical School, University College London.
In the interview
below,
ScienceWatch.com
talks with Dr. Ralevic about this paper and its impact on
the research community.
What factors motivated you to write this
review?
The main aim of this review was to categorize some of the extensive
literature on endogenous purine receptors according to the new nomenclature
developed around cloned receptors. In the 10 years before the review was
published, 16 out of 19 different receptors for purines and pyrimidines
were cloned, including all four subtypes of adenosine P1 receptor, all
seven subtypes of P2X purine receptor, and five (out of eight) subtypes of
P2Y purine receptor. This contributed to a worldwide renewed interest in
purinergic signaling. Importantly, it led to the development of a new
nomenclature for purine receptors, based on the newly cloned receptors;
this superceded the established nomenclature, expanded and refined since
the first formal recognition of purine receptors by Professor Geoffrey
Burnstock in 1978.
"There is still an enormous amount
that we do not know about purine
receptors."
The field was moving so rapidly that a comprehensive review was timely. The
intention was that this review would be a useful reference article for both
experts in, and newcomers to, the field of purine research. The review is
coauthored with Geoffrey Burnstock, the "grandfather" of purinergic
signaling, and is a testimony to the time that I spent with him as a Ph.D.
student and postdoctoral research fellow.
Would you sum up the main points of your review for our
readers?
Purines and pyrimidines are important extracellular signaling molecules
that have diverse biological effects via cell-surface receptors known as
purine receptors. This review describes briefly the history of the
discovery of purine receptors, and details their current classification;
firstly into two main families of P1 and P2 receptors, with a further
subdivision of P1 receptors into four subtypes, and P2 receptors into P2X
receptors (seven subtypes) and P2Y receptors (now eight subtypes). The
review matches endogenous purine receptors, characterized mainly using
pharmacological, electrophysiological, and immunohistochemical methods,
with their cloned counterparts.
The review additionally reports the important and diverse biological
actions of purines and pyrimidines, including modulation of cardiac
function, smooth muscle contraction, neurotransmission, exocrine and
endocrine secretion, immune and inflammatory responses, pain, and platelet
aggregation. It seems that every single cell in the body expresses one or
more subtypes of purine receptor and is, therefore, regulated by purines
and pyrimidines.
How has our knowledge of these receptors changed in the
10 years since this paper was published?
There has been a tremendous increase in the breadth and depth of our
understanding of purine receptors in the last 10 years. Two further P2Y
receptors, P2Y12 and P2Y13, were cloned in 2001, and
the P2Y14 receptor was identified (it was first cloned in 1994
as an orphan receptor).
More generally, we are starting to know increasingly more about each of the
specific receptor subtypes: their tissue expression, signaling, regulation,
and patho/physiological roles. For example, the stoichiometry of P2X
receptors has been clearly defined as 3 subunits, and we now know that
adenosine P1 receptors (A1 subtype) can dimerize with certain
P2Y receptors (P2Y1 and P2Y2). Through the
development and use of knockout animals, small interference RNA and
subtype-selective ligands, patho/physiological roles of different purine
receptor subtypes have been newly identified or confirmed, including:
A1 receptors in regulation of pain, anxiety, neuroprotection and
tubuloglomerular feedback; A2A receptors in inflammation;
A3 receptors in immunity and ischemia-reperfusion injury;
P2X1 receptors in platelet aggregation, fertility and
reproduction and tubuloglomerular feedback; P2X2/3 receptors in
nociceptive and mechanosensory transduction; P2X4 receptors in
regulation of blood pressure and vascular remodeling; P2X7
receptors in inflammation and pain, bone formation and resorption;
P2Y1 receptors in platelet aggregation; P2Y2
receptors in epithelial chloride secretion in airways and potassium
secretion in the gastrointestinal tract; P2Y4 receptors in
epithelial potassium secretion in the gastrointestinal tract;
P2Y12 receptors in platelet aggregation and microglial
chemotaxis; P2Y13 receptors in regulation of hepatic HDL
endocytosis.
"Purines and pyrimidines are
important extracellular signaling molecules
that have diverse biological effects via
cell-surface receptors known as purine
receptors."
Changes in purine receptor expression have been shown in response to
physiological stimuli (e.g., noise upregulates expression of
P2X2 mRNA and protein in the cochlea), as well as in
development, ageing, and disease (e.g., P2X1 and P2Y2
receptor mRNA levels are increased in congestive heart failure). Some
premises have been overturned. For example, it had long been believed that,
in blood vessels, P2X receptors are expressed on the smooth muscle and P2Y
receptors on the endothelium; it is now known that different subtypes of
both P2X and P2Y receptors are expressed on both smooth muscle and
endothelium, with diverse roles in regulation of contractility, tissue
growth, and development. There is increasing evidence that these important
discoveries about purine receptors can be exploited clinically, e.g., in
the development and use of P2Y12 antagonists to inhibit platelet
aggregation, and in the development of P2Y2 antagonists to treat
chronic bronchitis, cystic fibrosis, and dry eye.
Are there things we still don’t know about these
receptors?
There is still an enormous amount that we do not know about purine
receptors. A number of the different receptor subtypes are still largely
enigmatic, mainly because of a lack of selective ligands and knockouts
available to give clues as to their physiological roles. Overall,
relatively little is known about the sources, stimuli, and mechanisms of
release and metabolism of the endogenous ligands of purine receptors,
especially of the pyrimidine nucleotides UTP and UDP. This limits our
understanding of purine receptors, through not knowing the circumstances
leading to their activation.
Our understanding of the physiological roles of purine receptors in humans
is still in its infancy compared to that in other species. Similarly,
although there is evidence of an involvement of purine receptors in many
different animal models of disease, including cardiac disease, immune and
inflammatory disorders, and cancer, relatively little is known about the
roles of purine receptors in pathophysiological conditions in humans.
What should the "take-away lesson" about your work
be?
It is clear that purines and pyrimidines, through actions on specific
purine receptors, have important and diverse effects on many different
biological processes. There is a rapidly growing increase in our
understanding of all aspects of purinergic signaling—especially the
expression, signaling mechanisms, and physiological roles of different
subtypes of purine receptors—which is being driven by the tantalizing
prospect that they can be targeted clinically.
Dr. Vera Ralevic
School of Biomedical Sciences
University of Nottingham
Nottingham, UK