Dual effects of muscarinic M 2 receptors on the synthesis of cyclic AMP in CHO cells : Background and model

Abstract

It has been observed in several laboratories that muscarinic agonists have dual effects on the synthesis of cyclic AMP in cell lines expressing muscarinic M 2 or M 4 receptors, producing strong inhibition at low agonist concentrations and lesser inhibition or stimulation at high agonist concentrations. Data obtained on CHO cells (known to express adenylyl cyclases VI and VII) are best interpreted on the assumption that the upward phase of the concentration-response curves reflects simultaneous inhibition of adenylyl cyclase VI via the Gi proteins, with which the M 2 and M 4 receptors communicate with high affinity, and stimulation of adenyly cyclases VI and VII via the Gs proteins, with which the M 2 and M 4 receptors communicate with low affinity. A simplified model is described which permits one to predict how the shapes of the concentration-response curves will be affected by changes in the concentration of receptors, the affinities of activated receptors for Gi or Gs proteins, and other parameters.