TY - JOUR
T1 - Heterologous desensitization and reduced G protein ADP-ribosylation following exposure to α2-adrenoceptor and muscarinic receptor agonists
AU - Nah, Seung Yeol
AU - Attali, Bernard
AU - Vogel, Zvi
N1 - Funding Information:
The authorsw ould like to thankD r. A. Spiegelo f the National Instituteos f Health,B ethesdaM, D, USA, and Dr. W. Rosenthaol f the Free Universityo f Berlin, Germanyf,o r theirg enerouds onation of antibodietso the G proteina subunitsW. e also thank Mrs. D. Sayaf or her excellentte chnicahl elp,and D. SchoenbergM,. S., for her criticalr eadinga nde ditingo f the manuscripTt.h is researchw as supportedb y the Israeli Anti-Drug Authority, the Minerva and SchillingF oundationsth, eN ationaIln stituteo f Drug Abuse,a ndthe German-lsraeFlio undationf or ScientificR esearcha nd Development. Z.V. is the incumbenot f the Ruth and Leonard Simon ProfessoriaCl hairin CancerR esearch.
PY - 1993/1/4
Y1 - 1993/1/4
N2 - We investigated the acute and chronic effects of α2-adrenoceptor and muscarinic receptor agonists on dihydropyridine-sensitive voltage-dependent Ca2+ channels in spinal cord-dorsal root ganglion cocultures. Clonidine and oxotremorine inhibited the voltage-dependent Ca2+ influx (42 ± 2% and 35 ± 6% with 100 μM, respectively). The respective antagonists, yohimbine and atropine, abolished these effects.Pertussis toxin attenuated the inhibitory effects of clonidine and oxotremorine on Ca2+ influx, demonstrating involvement of G proteins in the transduction process. Chronic treatment with clonidine or oxotremorine desensitized the Ca2+ channel response to the agonist applied as well as to other receptor agonist (heterologous desensitization). Such treatment with clonidine or oxotremorine decreased the pertussin toxin-catalyzed ADP-ribosylation of Giα and Goα subunits, an effect which could be largely reversed by the detergent Lubrol PX. Yohimbine and atropine blocked the effects of clonidine or oxotremorine on pertussis toxin-catalyzed ADP-ribosylation. Results suggest that α2-adrenoceptor and muscarinic receptors couple to the dihydropyridine-sensitive voltage-dependent Ca2+ channels via pertussis toxin-sensitive G proteins. Chronic agonist treatment leads to heterologous desensitization and to a reduced capacity of Gi and Go to undergo pertussis toxin-catalyzed ADP-ribosylation.
AB - We investigated the acute and chronic effects of α2-adrenoceptor and muscarinic receptor agonists on dihydropyridine-sensitive voltage-dependent Ca2+ channels in spinal cord-dorsal root ganglion cocultures. Clonidine and oxotremorine inhibited the voltage-dependent Ca2+ influx (42 ± 2% and 35 ± 6% with 100 μM, respectively). The respective antagonists, yohimbine and atropine, abolished these effects.Pertussis toxin attenuated the inhibitory effects of clonidine and oxotremorine on Ca2+ influx, demonstrating involvement of G proteins in the transduction process. Chronic treatment with clonidine or oxotremorine desensitized the Ca2+ channel response to the agonist applied as well as to other receptor agonist (heterologous desensitization). Such treatment with clonidine or oxotremorine decreased the pertussin toxin-catalyzed ADP-ribosylation of Giα and Goα subunits, an effect which could be largely reversed by the detergent Lubrol PX. Yohimbine and atropine blocked the effects of clonidine or oxotremorine on pertussis toxin-catalyzed ADP-ribosylation. Results suggest that α2-adrenoceptor and muscarinic receptors couple to the dihydropyridine-sensitive voltage-dependent Ca2+ channels via pertussis toxin-sensitive G proteins. Chronic agonist treatment leads to heterologous desensitization and to a reduced capacity of Gi and Go to undergo pertussis toxin-catalyzed ADP-ribosylation.
KW - ADP ribosylation
KW - Ca channels
KW - GTP-binding proteins
KW - Heterologous desensitization
KW - Muscarinic receptors
KW - α-Adrenoceptors
UR - http://www.scopus.com/inward/record.url?scp=0027393569&partnerID=8YFLogxK
U2 - 10.1016/0922-4106(93)90060-M
DO - 10.1016/0922-4106(93)90060-M
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AN - SCOPUS:0027393569
VL - 244
SP - 67
EP - 75
JO - European Journal of Pharmacology - Molecular Pharmacology Section
JF - European Journal of Pharmacology - Molecular Pharmacology Section
SN - 0922-4106
IS - 1
ER -