Agonist unbinding from receptor dictates the nature of deactivation kinetics of G protein-gated K ⁺ channels

This is the authors' abstract. We don't add key points for this paper.

G protein-gated inwardly rectifying K(+) (Kir) channels are found in neurones, atrial myocytes, and endocrine cells and are involved in generating late inhibitory postsynaptic potentials, slowing the heart rate and inhibiting hormone release. They are activated by G protein-coupled receptors (GPCRs) via the inhibitory family of G protein, G(i/o), in a membrane-delimited fashion by the direct binding of Gbetagamma dimers to the channel complex. In this study we are concerned with the kinetics of deactivation of the cloned neuronal G protein-gated K(+) channel, Kir3.1 + 3.2A, after stimulation of a number of GPCRs. Termination of the channel activity on agonist removal is thought to solely depend on the intrinsic hydrolysis rate of the G protein alpha subunit. In this study we present data that illustrate a more complex behavior. We hypothesize that there are two processes that account for channel deactivation: agonist unbinding from the GPCR and GTP hydrolysis by the G protein alpha subunit. With some combinations of agonist/GPCR, the rate of agonist unbinding is slow and rate-limiting, and deactivation kinetics are not modulated by regulators of G protein-signaling proteins. In another group, channel deactivation is generally faster and limited by the hydrolysis rate of the G protein alpha subunit. G protein isoform and interaction with G protein-signaling proteins play a significant role with this group of GPCRs.

No immediate clinical implications from animal data; extends kinetic models of GPCR-G protein signaling.