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PMID: 2541856 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

An investigation into the mechanisms of inhibition of calcium channel currents in cultured sensory neurones of the rat by guanine nucleotide analogues and (-)-baclofen.

British journal of pharmacology ·Vol. 97 ·No. 1 ·1989-05-00 ·Pages 263-73

Dolphin AC, McGuirk SM, Scott RH

Abstract

1. The mechanism of inhibition of calcium channel currents by the guanine nucleotide analogue guanosine 5'-O-3 thiotriphosphate (GTP-gamma-S) and by the GABAB agonist (-)-baclofen has been studied in cultured dorsal root ganglion neurones of the rat. The inhibition by GTP-gamma-S is particularly characterized by an abolition of the transient component of calcium channel currents carried either by Ba2+ (IBa) or by Ca2+ (ICa). 2. The effect of agents increasing intracellular cyclic AMP levels has been examined. Neither internal cyclic AMP nor forskolin prevented the inhibition of IBa by baclofen. Neither forskolin nor pretreatment of cells with cholera toxin prevented the inhibition of the transient component of IBa by GTP-gamma-S. However, both these treatments increased the amplitude of the sustained IBa in the presence of GTP-gamma-S. The ATP analogue adenosine imido-diphosphate which inhibits many ATP requiring enzymes did not prevent the effect of GTP-gamma-S although it reduced the amplitude of IBa. 3. Baclofen (100 microM) produced a 22 +/- 2% increase in inositol phosphate production in 30 s, whereas the increase produced by bradykinin (1 microM) was 70 +/- 14%. However, unlike baclofen, bradykinin did not inhibit IBa or ICa in these cells. 4. The effect of protein kinase C inhibitors was examined. Polymixin B (20 microM in patch pipette) had no effect on the inhibition of IBa by baclofen or GTP-gamma-S. A higher concentration (100 microM) alone inhibited IBa and no further inhibition by baclofen was observed. Neither H7 (50 microM) nor staurosporine (100 nM), applied extracellularly, prevented the response to GTP-gamma-S. 5. The protein kinase C activator di-octanoyl glycerol (20 microM) did not inhibit IBa. Arachidonic acid (100 microM) also produced no inhibition of IBa. 6. In conclusion we have obtained no evidence that a second messenger system mediates the inhibition of calcium channel currents by GTP-gamma-S or baclofen in dorsal root ganglion neurones. These results support the hypothesis that GABAB receptors are directly coupled to calcium channels by G proteins.

MeSH Terms
Animals Arachidonic Acid Arachidonic Acids/pharmacology Baclofen/pharmacology Calcium Channels/drug effects,metabolism Cells, Cultured Cholera Toxin/pharmacology Colforsin/pharmacology Culture Techniques Electrophysiology Enzyme Activation/drug effects Guanine Nucleotides/pharmacology Guanosine 5'-O-(3-Thiotriphosphate) Guanosine Triphosphate/analogs & derivatives,pharmacology Neurons, Afferent/drug effects,metabolism Protein Kinase C/biosynthesis Rats Thionucleotides/pharmacology Type C Phospholipases/metabolism
Chemicals
Arachidonic Acids Calcium Channels Guanine Nucleotides Thionucleotides Colforsin Arachidonic Acid Guanosine 5'-O-(3-Thiotriphosphate) Guanosine Triphosphate Cholera Toxin Protein Kinase C Type C Phospholipases Baclofen
Authors & Affiliations
3 authors, click to expand affiliations / ORCID
Dolphin A C
Department of Pharmacology, St. George's Hospital Medical School, London.
McGuirk S M
Scott R H
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45 references, click to expand
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Article Info
Journal
British journal of pharmacology
Abbr.
Br J Pharmacol
ISSN
0007-1188
DOI
10.1111/j.1476-5381.1989.tb11950.x
Published
1989-05-00
Pages
263-73
Language
English
Region
England
NLM ID
7502536
PMCID
PMC1854493
Subset
IM
Grants
Wellcome Trust · United Kingdom
External Links
PubMed source DOI: 10.1111/j.1476-5381.1989.tb11950.x PMC Full Text View journal details
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