Activation of Muscarinic Potassium Currents by ATP Gamma S in Atrial Cells

Intracellular perfusion of atrial myocytes with adenosine 5'-(gamma-thio) triphosphate (ATP gamma S), an ATP analog, elicits a progressive increase of the muscarinic potassium channel current, IK(M), in the absence of agonists. In this respect, ATP gamma S mimics the actions of guanosine triphosphate (GTP) analogs, which produce direct, persistent activation of the guanyl nucleotide-binding (G) protein controlling the K+(M) channel. The effect of ATP gamma S on IK(M), however, differs from that produced by GTP analogs in two aspects: it requires relatively large ATP gamma S concentrations, and it appears after a considerable delay, suggesting a rate-limiting step not present in similar experiments performed with guanosine 5'-(gamma-thio) triphosphate (GTP gamma S). Incubation of atrial homogenates with [35S]ATP gamma S leads to formation of significant amounts of [35S]GTP gamma S, suggesting that activation of IK(M) by ATP gamma S arises indirectly through its conversion into GTP gamma S by cellular enzymes. ATP gamma S is often used to demonstrate the involvement of protein phosphorylation in the control of various cellular processes. The finding that cytosolic application of ATP gamma S can also lead to G-protein activation implies that experiments with ATP gamma S must be interpreted with caution.