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J. Biol. Chem., Vol. 276, Issue 37, 34853-34861, September 14, 2001
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From G protein-coupled receptors are thought to
mediate agonist-evoked signal transduction by interconverting between
discrete conformational states endowed with different pharmacological
and functional properties. In order to address the question of multiple receptor states, we monitored rapid kinetics of fluorescent neurokinin A (NKA) binding to tachykinin NK2 receptors, in parallel with intracellular calcium, using rapid mixing equipment connected to real
time fluorescence detection. Cyclic AMP accumulation responses were
also monitored. The naturally truncated version of neurokinin A
(NKA-(4-10)) binds to the receptor with a single rapid phase and evokes only calcium responses. In contrast, full-length NKA binding
exhibits both a rapid phase that correlates with calcium responses and
a slow phase that correlates with cAMP accumulation. Furthermore,
activators (phorbol esters and forskolin) and inhibitors (Ro 31-8220 and H89) of protein kinase C or A, respectively, exhibit differential
effects on NKA binding and associated responses; activated protein
kinase C facilitates a switch between calcium and cAMP responses,
whereas activation of protein kinase A diminishes cAMP responses. NK2
receptors thus adopt multiple activatable, active, and desensitized
conformations with low, intermediate, or high affinities and with
distinct signaling specificities.
The Neurokinin A Receptor Activates Calcium and cAMP Responses
through Distinct Conformational States*
§,§,§,§,
, and§**
CNRS UPR 9050, Ecole Supérieure de
Biotechnologie de Strasbourg, Boulevard Sébastien Brant,
67400 Illkirch, France, ¶ Pharmacologie et
Physico-Chimie des Interactions Cellulaires et Moléculaires,
Faculté de Pharmacie 74, Route du Rhin, BP 24 67401 Illkirch, France, § Institut Fédératif
de Recherche IFR 85 et FR 2059, 67400 Illkirch, France, and
the Department of Biochemistry, 30 Quai
Ernest-Ansermet, CH-1211 Geneva 4, Switzerland
*
This work was supported by CNRS, INSERM, the Association
pour la Recherche sur le Cancer, the Fondation pour la Recherche Médicale, the Ligue Nationale Contre le Cancer (Comité du
Haut-Rhin), the Agence Nationale pour la Recherche sur le SIDA, the
Université Louis Pasteur de Strasbourg, and SIDACTION (to
T. P.).The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
Copyright © 2001 by The American Society for Biochemistry and Molecular Biology, Inc.
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