Bimodal regulation of cyclic AMP by muscarinic receptors. Involvement of multiple G proteins and different forms of adenylyl cyclase

Life Sci. 1995;56(11-12):973-80. doi: 10.1016/0024-3205(95)00036-6.


In membranes of rat olfactory bulb, muscarinic receptor agonists stimulate basal adenylyl cyclase activity . This response is inhibited by a number of muscarinic receptor antagonists with a rank order of potency suggesting the involvement of the M4 muscarinic receptor subtype. The stimulatory effect does not require Ca2+ and occurs independently of activation of phosphoinositide hydrolysis. Pretreatment with pertussis toxin completely prevents the muscarinic stimulation of adenylyl cyclase, indicating the participation of G proteins of the Gi/Go family. Immunological impairment of the G protein, Gs, also reduces the muscarinic response, whereas concomitant activation of Gs-coupled receptors by CRH or VIP results in a synergistic stimulation of adenylyl cyclase activity. Although these data suggest a role for Gs, a body of evidence indicates that the muscarinic receptors do not interact directly with this G protein. Moreover, the Ca2+/calmodulin (Ca2+/CaM)- and forskolin-stimulated enzyme activities are inhibited by muscarinic receptor activation in a pertussis toxin-sensitive manner and with a pharmacological profile similar to that observed for the stimulatory response. These data indicate that in rat olfactory bulb M4 muscarinic receptors exert a bimodal control on cyclic AMP formation through a sequence of events that may involve activation of Gi/Go proteins, synergistic interaction with Gs and differential modulation of Ca2+/CaM-independent and -dependent forms of adenylyl cyclase.

Publication types

  • Comparative Study

MeSH terms

  • Acetylcholine / pharmacology
  • Adenylyl Cyclases / immunology
  • Adenylyl Cyclases / metabolism*
  • Animals
  • Calcium-Calmodulin-Dependent Protein Kinases / metabolism
  • Carbachol / pharmacology
  • Colforsin / pharmacology
  • Cyclic AMP / metabolism*
  • GTP-Binding Proteins / metabolism*
  • Heart / drug effects
  • Inositol Phosphates / metabolism
  • Male
  • Muscarinic Agonists / pharmacology
  • Muscarinic Antagonists / pharmacology
  • Myocardium / enzymology
  • Neostriatum / drug effects
  • Neostriatum / enzymology
  • Olfactory Bulb / drug effects
  • Olfactory Bulb / enzymology
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, Muscarinic / drug effects
  • Receptors, Muscarinic / immunology
  • Receptors, Muscarinic / metabolism*
  • Signal Transduction


  • Inositol Phosphates
  • Muscarinic Agonists
  • Muscarinic Antagonists
  • Receptors, Muscarinic
  • Colforsin
  • Carbachol
  • Cyclic AMP
  • Calcium-Calmodulin-Dependent Protein Kinases
  • GTP-Binding Proteins
  • Adenylyl Cyclases
  • Acetylcholine