Magnesium Ions Exert a Central Role in Integrating Adenosine Receptor Occupancy with the Inhibition of Adenylate Cyclase

Abstract

The adenosine receptors associated with the adipocyte and brain cortex adenylate cyclase are typical of those neurotransmitter receptors that inhibit the enzyme’s activity in numerous tissues (1). This receptor regulates enzyme activity through a GTP regulatory protein complex (N_i) that is distinct from that which mediates stimulation of the enzyme (N_s) (2–7). The GTP regulatory complex modulates enzyme activity via a GTP hydrolytic cycle involving heterotropic interactions with the receptor and catalytic unit (8–13). Considerable progress has recently been made on characterizing the two types of GTP regulatory complex. Both appear to be comprised of at least three subunits, one of which is unique and two that are common to both complexes. The unique subunit associated with N. can be ADP-ribosylated by islet-activating protein (IAP) a toxin elicited by Bordetella pertussis (7,14,15). At present, the most direct evidence that the IAP substrate is a functional component of N_i mediating hormone inhibition is the demonstration of attenuation of hormonal inhibition by IAP and the reversal of this attenuation by the addition of exogenous (non-treated) IAP substrate (14–16). Such evidence clearly supports a role for the IAP substrate in an N_i complex, although it does not exclude the possibility that other subunits might be required for the promotion of hormonal inhibition.