Neurotransmission can be regulated at several levels, including the rate of neurotransmitter release, the availability of receptors on the postsynaptic membrane and the activities of downstream signalling pathways. In a paper published in the Journal of Neuroscience, Delling et al. now show that an adhesion molecule can regulate the lipid-raft-dependent trafficking of an ion channel, and this might provide a new mechanism for controlling synaptic transmission.

It was previously shown that, in mice deficient in the neural cell-adhesion molecule NCAM, the serotonin 5-HT1A receptor becomes more responsive to certain agonists than that of wild-type littermates. However, there was no evidence that NCAM affects the expression or function of the receptor itself, so Delling et al. turned their attention to another component of the signalling pathway.

The signalling activity of the 5-HT1A receptor is mediated through the inwardly rectifying potassium channel Kir3, and the authors showed that Kir3 currents were increased in the absence of NCAM. However, NCAM did not affect the overall expression levels of Kir3, nor did it seem to alter the conductance of individual channels. By transfecting NCAM and Kir3 RNA into Xenopus oocytes and neurons, Delling et al. showed that in the presence of NCAM, fewer of the Kir3 channels became localized to the cell membrane, indicating that this adhesion molecule blocks the transport of these channels to the cell surface.

So, how does NCAM prevent the channel from reaching its destination? An important clue came from the observation that both NCAM and Kir3 are associated with lipid rafts — cholesterol-rich lipid domains that are used to transport proteins around the cell and to organize signalling complexes on the membrane. NCAM can be modified by the lipid palmitate, and only the palmitoylated form can associate with lipid rafts. Delling et al. found that if they removed the palmitoylation site from the NCAM molecule, the delivery of Kir3 channel subunits to the membrane was increased, indicating that the association of NCAM with lipid rafts somehow prevents these rafts from delivering Kir3 channels to the cell surface.

The precise mechanism by which NCAM regulates Kir3 trafficking is not yet clear, and this will be an important question to address in the future. It will also be interesting to find out whether the trafficking of other signalling molecules is regulated in the same way, opening up a whole raft of possibilities for future study.