Stargazin is best known for helping to ferry receptor proteins to the surface of neurons. The discovery that it has an unexpected additional role has widespread implications for the way that neurons talk to each other.
Cognition relies on the fast transmission of excitatory signals between neurons. To achieve this, neurotransmitters such as glutamate are released from one neuron into the synapse (the junction between neurons) where they are picked up by receptors on the opposing ‘postsynaptic’ cell. Glutamate receptors called AMPARs form ion channels embedded in the cell membrane that, upon binding of glutamate, open rapidly to allow cations to flood into the neuron — converting the chemical signal from the neurotransmitter into an electrical pulse. In this issue, Tomita et al. (page 1052)1 show that an accessory protein that helps to shuttle AMPARs into the membrane does double-duty to amplify the effectiveness with which glutamate opens the channel. AMPARs are among the most intensively studied of the neurotransmitter ion channels, so this discovery of an ‘overlooked’ accessory subunit is quite a surprise.
Tomita et al.1 describe a functional analysis of the membrane-spanning protein Stargazin, which until recently was known only as a regulator that helped move AMPARs into the cell membrane. Their work shows that Stargazin can also control two key aspects of receptor function: the overall flux of ions through the water-filled AMPAR pore, and the ability of the receptor to function in the continued presence of glutamate, such as might occur during rapid neuronal firing. This finding, which has been corroborated by other recent studies2,3, could have widespread implications for the way that neurons in the brain not only talk to each other, but how they increase or decrease their volume and change their pitch — features by which the brain may encode memory.
This is not the first time that Stargazin has surprised neuroscientists by having functions other than those initially proposed for it. Stargazin was originally discovered as a neuronal protein expressed from a gene mutated in the epileptic Stargazer mutant mouse4, and sequence analysis suggested it was a calcium-channel subunit. Then, it was the first integral membrane protein discovered to interact with AMPARs5. Subsequently, Stargazin and its family members were found to be necessary partners for AMPARs, both during transport to the neuronal membrane and the subsequent positioning of the receptors at synaptic sites. Highly coordinated spatiotemporal changes in the synaptic content of AMPARs are a principal mechanism by which the brain regulates synaptic strength. This activity-dependent regulation of excitatory signalling strength is considered a prime candidate for the biological mechanism underlying memory. Stargazin associates with AMPARs in an intracellular compartment near the cell membrane to chaperone their delivery to the neuronal surface, for example during changes in synaptic strength (Fig. 1).
Stargazin seems to remain in complex with AMPAR after delivery6,7, indicating that most neuronal AMPARs are always in association with Stargazin or other family members. In this study, Tomita et al.1 explore the potential contributions of Stargazin to AMPAR function once the receptor reaches the synaptic membrane (Fig. 1). They found that increases in the density of AMPARs at the cell surface could not entirely account for increases in the cell's functional responses to glutamate in the presence of Stargazin. An analysis of the kinetics of AMPAR function showed that the presence of Stargazin reduces the amount of time the receptor spends in the ‘desensitized’ state. In this state, glutamate remains tightly bound to the receptor, but the ion-conducting pore rarely opens. Moreover, the functional steps where the receptor closes its channel and glutamate unbinds also slowed in the presence of Stargazin (see also ref. 2).
These effects imply that Stargazin alters the ease with which the pore opens (referred to as gating) after glutamate binding (Fig. 1). Gating is defined as the conformational changes in the glutamate-bound receptor as energy gained from the interaction of glutamate with its binding site is used to open the ion channel. Recordings of currents from single channels indeed showed that in the presence of Stargazin, glutamate-bound AMPAR more frequently opens into high-conducting conformations — indicative of increased gating efficiency. Stargazin in native AMPARs should therefore enhance the efficiency with which glutamate released from nerve terminals can depolarize a postsynaptic neuron. This prediction was confirmed through experimentation with a mutated version of Stargazin that was unable to regulate AMPAR function but could facilitate AMPAR trafficking.
This new role for Stargazin raises obvious questions about previous kinetic and structural studies that used experimental systems lacking Stargazin or its siblings. In addition, it has become even more important to determine whether results obtained with recombinant receptors (produced from introduction of cloned DNA into cells) accurately reflect what happens with native neuronal receptors. There are also several complex questions that need to be answered about the accessory function of Stargazin. What factors control the size and nature of the AMPAR ion-conducting pore, and how does Stargazin regulate these factors? Can Stargazin's actions on permeation and gating themselves be regulated? Stargazin and other members of its family have discrete expression patterns in different regions of the central nervous system. Does such heterogeneity contribute to regional or developmental difference in AMPAR roles?
As always, much remains to be done to answer these and other questions. But for the moment, the uncovering of Stargazin's ability to regulate AMPAR function itself reminds us to expect surprises from even the best-studied systems. Who knows how many more crucial functions hide among proteins we think we understand?
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Nature Neuroscience (2009)