G protein-gated K+ channels (GIRK, Kir3), activated by Gxcexb2xcexb3 subunits derived from Gi/o proteins, regulate heartbeat and neuronal excitability and plasticity. Both neurotransmitter-evoked (Ievoked) and neurotransmitter-independent basal (Ibasal) GIRK activities are physiologically important, but mechanisms of Ibasal and its relation to Ievoked are unclear. We have previously shown for heterologously expressed neuronal GIRK1/2, and now show for native GIRK in hippocampal neurons, that Ibasal and Ievoked are interrelated: the extent of activation by neurotransmitter (activation index, Ra) is inversely related to Ibasal. To unveil the underlying mechanisms, we have developed a quantitative model of GIRK1/2 function. We characterized single-channel and macroscopic GIRK1/2 currents, and surface densities of GIRK1/2 and Gxcexb2xcexb3 expressed in Xenopus oocytes. Based on experimental results, we constructed a mathematical model of GIRK1/2 activity under steady-state conditions before and after activation by neurotransmitter. Our model accurately recapitulates Ibasal and Ievoked in Xenopus oocytes, HEK293 cells and hippocampal neurons, correctly predicts the dose-dependent activation of GIRK1/2 by coexpressed Gxcexb2xcexb3 and fully accounts for the inverse Ibasal-Ra correlation. Modeling indicates that, under all conditions and at different channel expression levels, between 3 and 4 Gxcexb2xcexb3 dimers are available for each GIRK1/2 channel. In contrast, available Gxcexb1i/o decreases from ~2 to less than one Gxcexb1 per channel as GIRK1/2s density increases. The persistent Gxcexb2xcexb3/channel (but not Gxcexb1/channel) ratio support a strong association of GIRK1/2 with Gxcexb2xcexb3, consistent with recruitment to the cell surface of Gxcexb2xcexb3, but not Gxcexb1, by GIRK1/2. Our analysis suggests a maximal stoichiometry of 4 Gxcexb2xcexb3 but only 2 Gxcexb1i/o per one GIRK1/2 channel. The unique, unequal association of GIRK1/2 with G protein subunits, and the cooperative nature of GIRK gating by Gxcexb2xcexb3, underlie the complex pattern of basal and agonist-evoked activities and allow GIRK1/2 to act as a sensitive bidirectional detector of both Gxcexb2xcexb3 and Gxcexb1. 