UC San Diego

Balancing inhibitory and excitatory inputs is essential for proper signaling in the brain. A significant component of inhibition involves the G protein-gated inwardly rectifying potassium (GIRK/Kir3) channels. GIRK channels have been shown to play a role in learning, pain sensation and drug addiction. Little is known about mechanisms for regulating the trafficking of GIRK channels. Using a proteomics approach, we have identified a unique rodent intracellular protein, sorting nexin 27 (SNX27), which regulates the trafficking of GIRK channels. SNX27 promotes the endosomal movement of GIRK channels, leading to reduced surface expression, increased degradation and smaller GIRK potassium currents. The regulation of endosomal trafficking via sorting nexins reveals a previously unknown mechanism for controlling potassium channel surface expression. We further describe the first agonist dependent regulation of these channels. Using immunohistochemistry at both light and electron microscopic levels, we discovered that chronic (24 hr) morphine treatment increases the colocalization of GIRK2 and PSD95 within dendritic spines. This change in expression requires activation of CaMKII and is mimicked by constitutively active form of this enzyme. The net effect of morphine treatment and CaMKII activation is to reduce the amplitude of GABAB receptor-activated GIRK currents. Our results demonstrate that stimulation of opioid receptors produces a form of CaMKII-dependent plasticity for the GABAB receptor-GIRK channel inhibitory pathway in the hippocampus. Both of these studies demonstrate changes in GIRK expression and may establish an important link between trafficking of potassium channels and drug actions in the brain, possibly opening up new avenues for treating drug addictions