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PMID: 9651200 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

P2Y2 nucleotide receptors expressed heterologously in sympathetic neurons inhibit both N-type Ca2+ and M-type K+ currents.

The Journal of neuroscience : the official journal of the Society for Neuroscience ·Vol. 18 ·No. 14 ·1998-07-15 ·Pages 5170-9

Filippov AK, Webb TE, Barnard EA, Brown DA

Abstract

The P2Y2 receptor is a uridine/adenosine triphosphate (UTP/ATP)-sensitive G-protein-linked nucleotide receptor that previously has been reported to stimulate the phosphoinositide signaling pathway. Messenger RNA for this receptor has been detected in brain tissue. We have investigated the coupling of the molecularly defined rat P2Y2 receptor to neuronal N-type Ca2+ channels and to M-type K+ channels by heterologous expression in rat superior cervical sympathetic (SCG) neurons. After the injection of P2Y2 cRNA, UTP inhibited the currents carried by both types of ion channel. As previously reported [Filippov AK, Webb TE, Barnard EA, Brown DA (1997) Inhibition by heterologously expressed P2Y2 nuerones. Br J Pharmacol 121:849-851], UTP inhibited the Ca2+ current (ICa(N)) by up to 64%, with an IC50 of approximately 0.5 microM. We now find that UTP also inhibited the K+M current (IK(M)) by up to 61%, with an IC50 of approximately 1.5 microM. UTP had no effect on either current in neurons not injected with P2Y2 cRNA. Structure-activity relations for the inhibition of ICa(N) and IK(M) in P2Y2 cRNA-injected neurons were similar, with UTP >/= ATP > ITP >> GTP,UDP. However, coupling to these two channels involved different G-proteins: pretreatment with Pertussis toxin (PTX) did not affect UTP-induced inhibition of IK(M) but reduced inhibition of ICa(N) by approximately 60% and abolished the voltage-dependent component of this inhibition. In unclamped neurons, UTP greatly facilitated depolarization-induced action potential discharges. Thus, the single P2Y2 receptor can couple to at least two G-proteins to inhibit both Ca2+N and K+M channels with near-equal facility. This implies that the P2Y2 receptor may induce a broad range of effector responses in the nervous system.

MeSH Terms
Animals Calcium Channels/physiology GTP-Binding Proteins/metabolism Membrane Potentials/drug effects,physiology Neurons/chemistry Pertussis Toxin Potassium Channels/physiology Rats Receptors, Purinergic P2/analysis Receptors, Purinergic P2Y2 Superior Cervical Ganglion/chemistry,cytology Uridine Triphosphate/pharmacology Virulence Factors, Bordetella/pharmacology
Chemicals
Calcium Channels P2ry2 protein, rat Potassium Channels Receptors, Purinergic P2 Receptors, Purinergic P2Y2 Virulence Factors, Bordetella Pertussis Toxin GTP-Binding Proteins Uridine Triphosphate
Authors & Affiliations
4 authors, click to expand affiliations / ORCID
Filippov A K
Department of Pharmacology, University College London, London WC1E 6BT, United Kingdom.
Webb T E
Barnard E A
Brown D A
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Article Info
Journal
The Journal of neuroscience : the official journal of the Society for Neuroscience
Abbr.
J Neurosci
ISSN
0270-6474
Published
1998-07-15
Pages
5170-9
Language
English
Region
United States
NLM ID
8102140
PMCID
PMC6793489
Subset
IM
Grants
Wellcome Trust · United Kingdom
External Links
PubMed source PMC Full Text View journal details
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