IDENTIFICATION AND CHARACTERIZATION OF MUSCARINIC RECEPTORS POTENTIATING THE STIMULATION OF ADENYLYL-CYCLASE ACTIVITY BY CORTICOTROPIN-RELEASING HORMONE IN MEMBRANES OF RAT FRONTAL-CORTEX
P. Onali et Mc. Olianas, IDENTIFICATION AND CHARACTERIZATION OF MUSCARINIC RECEPTORS POTENTIATING THE STIMULATION OF ADENYLYL-CYCLASE ACTIVITY BY CORTICOTROPIN-RELEASING HORMONE IN MEMBRANES OF RAT FRONTAL-CORTEX, The Journal of pharmacology and experimental therapeutics, 286(2), 1998, pp. 753-759
In membranes of the rat frontal cortex, acetylcholine (ACh) and other
cholinergic agonists were found to potentiate the stimulation of adeny
lyl cyclase activity elicited by corticotropin-releasing hormone (CRH)
. Oxotremorine-M, carbachol and methacholine were as effective as ACh,
whereas oxotremorine and arecoline were much less effective. The faci
litating effect of Ach was potently blocked by the M-1 antagonists R-t
rihexyphenidyl, telenzepine and pirenzepine and by the M-3 antagonists
hexahydro-sila-difenidol and p-fluorohexahydro-sila-difenidol, wherea
s the M-2 and M-4 antagonists himbacine, methoctramine, AF-DX 116 and
AQ-RA 741 were less potent. The mamba venom toxin MT-1, which binds wi
th high affinity to M-1 receptors, was also a potent blocker. The phar
macological profile of the muscarinic potentiation of CRH receptor act
ivity was markedly different from that displayed by the muscarinic inh
ibition of forskolin-stimulated adenylyl cyclase, which could be detec
ted in the same membrane preparations. Moreover, the intracerebral inj
ection of pertussis toxin impaired the muscarinic inhibition of cyclic
AMP formation and reduced the Ach stimulation of [S-35]GTP gamma S bi
nding to membrane G proteins but failed to affect the facilitating eff
ect on CRH receptor activity. The latter response was also insensitive
to the phospholipase C inhibitor U-73122, the protein kinase inhibito
r staurosporine and to the inhibitors of arachidonic acid metabolism i
ndomethacin and nordihydroguaiaretic acid. These data demonstrate that
in the rat frontal cortex, muscarinic receptors of the M-1 subtype po
tentiate CRH transmission by interacting with pertussis toxin-insensit
ive G proteins.