HIGHLIGHTS

NEURODEGENERATION ION CHANNELS CREB, the cell-death solution The Sigma K Fraternity

The cyclic-AMP-responsive element CREM in neuronal survival, and to The so-called sigma (CRE)-binding (CREB) fam- move on to think about their pos- has been ily of factors has been sible downstream . But in a something of a mystery implicated in many processes, includ- related paper, Lonze et al. remind us molecule for some time. ing memory formation and main- of the complexity of CREB regula- First described as an tenance, circadian rhythms and cell tion. They show that the redundant opioid receptor, it was survival in vitro. Two papers now function that was observed in the later found to interact show a crucial role for CREB-family CNS is not mirrored in the periph- with many types of drug members in cell survival in vivo in ery, by reporting that mice carrying a and to affect the nervous, both the central (CNS) and periph- null mutation in Creb1 show exces- endocrine and immune eral nervous systems, and provide sive apoptosis and degeneration of systems. One example of further support for the postulated sensory neurons during develop- sigma receptor function is role of CREB in the pathogenesis of ment. In addition, Creb1–/– cultured its ability to mediate the polyglutamine diseases. sympathetic and sensory neurons modulatory effects of There are three members of the showed impaired neurotrophin- psychotropic compounds CREB family — CREB, CRE-modu- dependent survival and axonal on some ion channels. latory protein (CREM) and activat- extension. Like Mantamadiotis et al., New data from Aydar ing 1 (ATF1). Lonze and co-workers did not find et al. indicate that this These activate transcrip- abnormal degeneration in the CNS modulation might depend on direct protein–protein tion by binding to CREs in the during development; however, they interactions with the channel. regions of target genes. were not able to study mice after The authors expressed the voltage-gated K+ channels Kv1.4 Mantamadiotis et al. assessed the birth, because the Creb1–/– animals and Kv1.5 in Xenopus oocytes, and found that K+ currents were role of CREB in neuronal survival die perinatally. Nevertheless, Lonze affected by co-expression of the sigma receptor. The nature of the by knocking out Creb1 specifically et al. have succeeded in providing us modulation depended on whether a sigma receptor ligand was in the developing brain or in the with clues about the possible mecha- present or not: in the absence of ligand, the receptor accelerated postnatal forebrain of mice. nism of action of this transcription voltage-dependent channel inactivation and reduced current Although they found no obvious factor. They showed that CREB is amplitude; in its presence, the receptor decreased the peak phenotype in these animals, they phosphorylated on its main regula- current even further. did observe an upregulation of tory residue — serine 133 — during Co-immunoprecipitation studies in pituitary cells (in which CREM (but not of ATF1). To inves- a period in which neurons from the sigma receptors and K+ channels are known to interact) allowed tigate whether this upregulation superior cervical and dorsal root Aydar et al. to conclude that the two proteins were part of the compensated for the loss of CREB, ganglia are dependent on nerve same molecular complex. It is unclear whether their interaction they looked at the effect of knocking growth factor and neurotrophin 3 is direct; however, as the modulatory effect was preserved in the out Creb1 in a Crem–/– background, for survival. oocytes, a direct contact is likely, unless any further interacting and found extensive apoptosis of post- It remains possible that ATF1 proteins are also naturally present in their expression system. mitotic neurons during develop- could compensate for the lack of Which parts of the sigma receptor are involved in this ment, indicating that the two CREB and CREM in the CNS, and interaction? We don’t yet know, but the authors made two transcription factors might have a that both CREM and ATF1 partially observations that might help us to answer this question. First, the redundant effect on cell survival. compensate for CREB in the periph- receptor has two transmembrane domains (instead of one, as was Intriguingly, Mantamadiotis et al. ery. However, the results clearly previously thought). Second, both the amino and carboxyl also found specific and progressive show that CREB-family members termini of the protein face the cytoplasm. Gaining a clear picture postnatal neurodegeneration in are crucial for neuronal survival, of receptor topology should help us to discover the structural the CA1 and dentate gyrus of the and these data add fuel to the idea determinants of its interaction with other proteins. hippocampus, and in the dorsal that the characteristic neurodegen- As sigma receptors bind antipsychotic drugs, understanding striatum. It is possible that the simi- eration in Huntington’s disease their mechanism of action might have practical implications.At larity between the degeneration might be related to disruption of the same time, channel regulation by protein–protein interactions pattern in the dorsal striatum that the CREB-dependent expression deserves further attention, as it adds degrees of freedom to the way was observed in these mice and of cell-survival factors. in which ion channels govern neuronal function. that seen in Huntington’s disease is Michael Stebbins Juan Carlos López more than a coincidence, as there is Assistant Editor, Nature Genetics References and links some evidence that polyglutamine References and links ORIGINAL RESEARCH PAPER Aydar, E. et al. The sigma receptor as a ligand-regulated repeats can sequester some key ORIGINAL RESEARCH PAPERS Mantamadiotis, auxiliary potassium channel subunit. Neuron 34, 399–410 (2002) T. et al. Disruption of CREB function in brain leads FURTHER READING Lupardus, P. J. et al. Membrane-delimited coupling between sigma CREB effectors. to neurodegeneration. Nature Genet. 31, 47–54 receptors and K+ channels in rat neurohypophysial terminals requires neither G-proteins nor It would have been convenient to (2002) | Lonze, B. E. et al. Apoptosis, axonal ATP. J. Physiol. (Lond.) 526, 527–539 (2000) growth defects, and degeneration of peripheral WEB SITES draw simple conclusions about the neurons in mice lacking CREB. Neuron 34, Encyclopedia of Life Sciences: http://www.els.net/ redundant function of CREB and 371–385 (2002) sodium, calcium and potassium channels | voltage-gated potassium channels

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