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Vol. 60, Issue 6, 1375-1382, December 2001
Department of Pharmacology (A.-D.Q., R.A.N.), University of North
Carolina, Chapel Hill, North Carolina; and Departments of Pharmacology
(A.C.Z., P.A.I.) and Medicine (P.A.I.), University of California at San
Diego, La Jolla, California
The recently cloned canine P2Y11 receptor
(cP2Y11) and its human homolog (hP2Y11) were
stably expressed in Chinese hamster ovary cells (CHO-K1) and 1321N1
human astrocytoma cells, and their agonist selectivities and coupling
efficiencies to phospholipase C and adenylyl cyclase were assessed.
Adenosine triphosphate nucleotides were much more potent and
efficacious at the hP2Y11 receptor than their corresponding
diphosphates in promoting both inositol phosphate and cyclic AMP
accumulation. In contrast, adenosine diphosphate nucleotides were
considerably more potent at the cP2Y11 receptor than their
corresponding triphosphate analogs. The tri- versus diphosphate
specificity of the two receptors was further confirmed in studies using
Ca2+ mobilization as a measure of receptor activation under
conditions that minimized nucleotide degradation. Moreover,
2-methylthioadenosine-5'-triphosphate and
2-methylthioadenosine-5'-diphosphate were 58- and 75-fold more potent
than ATP and ADP, respectively, at the cP2Y11 receptor compared with only 2- to 3-fold more potent at the hP2Y11
receptor. Mutational analysis revealed that the change of Arg-265,
which is located at the juxtaposition of transmembrane domain 6 and the
third extracellular loop in the hP2Y11 receptor, to
glutamine in the cP2Y11 receptor is at least partly
responsible for the diphosphate selectivity but not the increased
sensitivity to 2-thioether-substituted adenine nucleotides at the
canine receptor. These results imply a key role for a positively
charged arginine residue in contributing to the recognition of
extracellular nucleotides by the P2Y11 receptor and perhaps
other P2Y receptors.
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