Activation of G-protein gated inwardly rectifying potassium (GIRK) channels, found in the brain, heart and endocrine tissue, leads to membrane hyperpolarisation which generates neuronal inhibitory postsynaptic potentials, slows the heart rate and inhibits hormone release. During stimulation of G_i/o-coupled receptors and subsequent channel activation it has been observed that the current desensitises. In this study we examine mechanisms underlying fast desensitisation of cloned heteromeric neuronal Kir3.1+3.2A and atrial Kir3.1+3.4 channels and also homomeric Kir3.0 currents in response to stimulation of several G_i/o-GPCRs expressed in HEK293 cells (adenosine A₁, adrenergic _2A, dopamine D_2S, M₄ muscarinic and GABAB_1b\2 receptors). We find that all agonist-induced currents displayed a similar degree of desensitisation except the A₁ adenosine receptor which exhibits an additional desensitising component. Using the non-hydrolysable GTP analogue, GTPS, we find that this is due to a receptor-dependent, G-protein-independent process. Using Ca²⁺ imaging we show that desensitisation is unlikely to be accounted for solely by phospholipase C activation and PIP₂ hydrolysis. We examine the contribution of the G-protein cycle and find that, firstly, agonist concentration is strongly correlated with degree of desensitisation. Secondly, competitive inhibition of GDP-GTP exchange by using non-hydrolysable GDPS, has 2-effects: a slowing of channel activation and an attenuation of the fast desensitisation phenomenon. Finally, using specific G subunits we show that ternary complexes with fast activation rates display more prominent desensitisation than those with slower activation kinetics. Together our data suggests that fast desensitisation of GIRK currents is accounted for by the fundamental properties of the G-protein cycle.