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The neurokinin A receptor activates calcium and cAMP responses through distinct conformational states.
- Source :
-
The Journal of biological chemistry [J Biol Chem] 2001 Sep 14; Vol. 276 (37), pp. 34853-61. Date of Electronic Publication: 2001 Jul 17. - Publication Year :
- 2001
-
Abstract
- 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.
- Subjects :
- Cell Line
Cyclic AMP-Dependent Protein Kinases physiology
Fluorescence
Humans
Inositol 1,4,5-Trisphosphate biosynthesis
Ligands
Neurokinin A metabolism
Protein Conformation
Protein Kinase C physiology
Receptors, Neurokinin-2 chemistry
Calcium metabolism
Cyclic AMP biosynthesis
Receptors, Neurokinin-2 physiology
Subjects
Details
- Language :
- English
- ISSN :
- 0021-9258
- Volume :
- 276
- Issue :
- 37
- Database :
- MEDLINE
- Journal :
- The Journal of biological chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 11459843
- Full Text :
- https://doi.org/10.1074/jbc.M104363200