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Vol. 287, Issue 2, 508-514, November 1998
Synaptic Pharmaceutical Corporation, Paramus, New Jersey
Functional characterization of the recombinant human
5-hydroxytryptamine7(a) (h5-HT7(a))
receptor isoform was performed using stably transfected
LM(tk
) cells. Expression levels of the
h5-HT7(a) receptor determined from saturation studies using
either a labeled agonist ([3H]5-HT) or antagonist
([3H]LSD) were very similar (Bmax = 160-190
fmol/mg protein), suggesting that all receptors may exist in the high
affinity (G protein-coupled) state. In intact cells, 5-HT produced a
concentration-dependent elevation of intracellular cAMP levels
([cAMP]i) with an EC50 value of 80 nM and a
maximal response of 5-fold increase above basal levels. The rank order
of agonist potencies in the second messenger assay paralleled their
rank order of binding affinities: 5-carboxamidotryptamine > 5-hydroxytryptamine 
5-methoxytryptamine > 8-hydroxy
N,N-dipropyl aminotetralin > sumatriptan. Agonist potencies
(EC50 values) to stimulate [cAMP]i were more
than 25-fold lower relative to their respective binding affinities
(Ki values) obtained in [3H]5-HT
competition assays. In contrast, antagonist potencies
(Kb values) to block 5-HT-stimulated
[cAMP]i were in close agreement with their corresponding
Ki values. These data may indicate low
efficiency of receptor-effector coupling to adenylate cyclase stimulation. Pretreatment of stably transfected cells with cholera toxin abolished the 5-HT-mediated elevation of [cAMP]i,
indicating that the 5-HT7(a) subtype directly interacts
with G
s protein(s) to activate adenylate cyclase(s).
Clonal cell lines stably expressing h5-HT7 receptor
isoforms will serve as valuable cellular models to study their function
and regulation, as well as assist in the development of selective
5-HT7 receptor agents to uncover the biological roles and
potential therapeutic applications of this novel receptor subtype.
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