Lidocaine Enhances Gαi Protein Function

Background: Local anesthetics inhibit several G protein-coupled receptors by interaction with the G[alpha]q protein subunit. It is not known whether this effect on G protein function can be extrapolated to other classes of G proteins. The authors investigated interactions of lidocaine with the human adenosine 1 receptor (hA1R)-coupled signaling pathway. Activated A1Rs couple to adenylate cyclase via the pertussis toxin sensitive G[alpha]i protein, thereby decreasing cyclic adenosine monophosphate formation. A1Rs are widely expressed and abundant in the spinal cord, brain, and heart. Interactions of LAs with the hA1R-coupled transduction cascade therefore might produce a broad range of clinically relevant effects.

Methods: The function of hA1Rs stably expressed in Chinese hamster ovary cells was determined with assays of cyclic adenosine monophosphate, receptor binding, and guanosine diphosphate/guanosine triphosphate [gamma]35S exchange by using reconstituted defined G protein subunits. Involvement of phosphodiesterase and G[alpha]i was characterized by using the phosphodiesterase inhibitor rolipram and pertussis toxin, respectively.

Results: Lidocaine (10-9-10-1 M) had no significant effects on agonist or antagonist binding to the hA1R or on receptor-G protein interactions. However, cyclic adenosine monophosphate levels were reduced significantly to 50% by the LAs, even in the absence of an A1R agonist or presence of an A1R antagonist. This effect was unaffected by rolipram (10 [mu]m), but abolished completely by pretreatment with pertussis toxin, which inactivates the G[alpha]i protein. Therefore, the main target site for LAs in this pathway is located upstream from adenylate cyclase.