The regulation of ambient levels of several endogenous GPCR agonists (e.g. adenosine, somatostatin) may exert a modulatory effect on large-scale neuronal networks through GIRK channel activation. This large-scale effect of neuromodulators is known as volume transmission. Moderate activation of GIRK channels in a population of neurons would be expected to dampen membrane excitability (Figure 3C). For instance, somatostatin acting via SST5 receptors may alter the oscillation behavior of thalamic networks through post-synaptic activation of GIRK channels, along with presynaptic inhibition126. Similarly endogenous adenosine may suppress gamma oscillations in the hippocampus127, possibly due to the selective expression of A1 receptors on pyramidal neurons, which also activate GIRK channels. Dopamine concentrations are difficult to measure after synaptic or dendritic release128 but can be modeled in the extracellular space based on known diffusion properties and uptake efficiency of surrounding cells. The transmitter encounters predominantly extrasynaptic DA autoreceptors on DA axons and heteroreceptors on neighboring cells. In this model the sphere of influence for high affinity DA receptors has a volume of several tens of μm3, and may therefore affect thousands of synapses of
