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VOL. 73 (4), 1127-1157, 2007 PHYSIOLOGICAL ROLE OF EXTRACELLULAR...

of P2Y receptors in different signalling pathways are interconnected
and it requires to be analyzed from an integrated point of view (12).
It should be emphasized the great contributions by the group of K.
Harden, E. Barnard, J.M. Boeynaems, J.T. Neary, M.P. Abbracchio
and more recently J.P. Gachet among others (13-16). Recent
evidences of homo- and heterodimerization of nucleotide receptors
have been reported. This fact provides new possibilities of signalling
and new pharmacological approaches (17). The family of metabo-
tropic P2Y receptors exhibits a very abundant presence in all neural
and glial cells, where more than one subtype co-exists. The
physiological nucleotide agonists of P2Y receptors are very diverse,
some of them such as P2Y1,12,13 are specific for ADP, P2Y11 is the only
one specific for ATP, others as P2Y2, P2Y4, and P2Y6 are activated
mainly by the pyrimidine nucleotides UTP and UDP. These
metabotropic receptors are coupled to G proteins and activate a
large variety of downstream cascades, such as PI3K, AKT, MAP
kinases, and recently it has been reported the glycogen synthase
kinase-3, GSK3, regulation. Glial cells, exhibit a broad diversity of
functional P2Y receptors, coupled to Gq or Gi proteins and signalling
to intracellular cascades related to survival and proliferation. Figure
1 shows the main signalling cascades described for the P2Y subtypes
and Table 1 summarises the agonists, antagonists and G proteins
coupling of the P2Y receptors subtypes.

As described for other seven helix G protein coupled receptors,
the possibility of P2Y metabotropic receptors forming homodimers
or heterodimers increases the signalling and modulation posibilities
and should be considered in the future (18).

Ionotropic P2X family

P2X ionotropic receptor family contains a total of seven subunits,
P2X1,2,3,4,5,6,7. They present simple structures, with only two
transmembrane helixes, internal amine and carboxy terminals and a
large extracellular domain where the nucleotide binding site is
located. It is widely accepted, although not completely demonstrated,
that a minimum of three subunits are required to obtain a functional
ionotropic receptor. As in most of the studied tissues more than one

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