Dual effects of muscarinic M-2 receptors on the synthesis of cyclic AMP inCHO cells - Background and model

It has been observed in several laboratories that muscarinic agonists have dual effects on the synthesis of cyclic AMP in cell lines expressing muscar inic M-2 or M-4 receptors, producing strong inhibition at low agonist conce ntrations and lesser inhibition or stimulation at high agonist concentratio ns. Data obtained on CHO cells (known to express adenylyl cyclases VI and V II) are best interpreted on the assumption that the upward phase of the con centration-response curves reflects simultaneous inhibition of adenylyl cyc lase VI via the Gi proteins, with which the M-2 and M-4 receptors communica te with high affinity, and stimulation of adenyly cyclases VI and VII via t he Gs proteins, with which the M-2 and M-4 receptors communicate with low a ffinity. A simplified model is described which permits one to predict how t he shapes of the concentration-response curves will be affected by changes in the concentration of receptors, the affinities of activated receptors fo r Gi or Gs proteins, and other parameters. (C) 2001 Elsevier Science Inc. A ll rights reserved.