The so-called sigma receptor has been something of a mystery molecule for some time. First described as an opioid receptor, it was later found to interact with many types of drug and to affect the nervous, endocrine and immune systems. One example of sigma receptor function is its ability to mediate the modulatory effects of psychotropic compounds on some ion channels. New data from Aydar et al. indicate that this modulation might depend on direct protein–protein interactions with the channel.

The authors expressed the voltage-gated K+ channels Kv1.4 and Kv1.5 in Xenopus oocytes, and found that K+ currents were affected by co-expression of the sigma receptor. The nature of the modulation depended on whether a sigma receptor ligand was present or not: in the absence of ligand, the receptor accelerated voltage-dependent channel inactivation and reduced current amplitude; in its presence, the receptor decreased the peak current even further.

Co-immunoprecipitation studies in pituitary cells (in which sigma receptors and K+ channels are known to interact) allowed Aydar et al. to conclude that the two proteins were part of the same molecular complex. It is unclear whether their interaction is direct; however, as the modulatory effect was preserved in the oocytes, a direct contact is likely, unless any further interacting proteins are also naturally present in their expression system. Which parts of the sigma receptor are involved in this interaction? We don't yet know, but the authors made two observations that might help us to answer this question. First, the receptor has two transmembrane domains (instead of one, as was previously thought). Second, both the amino and carboxyl termini of the protein face the cytoplasm. Gaining a clear picture of receptor topology should help us to discover the structural determinants of its interaction with other proteins.

As sigma receptors bind antipsychotic drugs, understanding their mechanism of action might have practical implications. At the same time, channel regulation by protein–protein interactions deserves further attention, as it adds degrees of freedom to the way in which ion channels govern neuronal function.