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Journal of Physiology (2002), 545.1, p. 2
© Copyright 2002 The Physiological Society
DOI: 10.1113/jphysiol.2002.033886

The 14-3-3 protein as a novel regulator of ion channel localisation

Masaru Ishii and Yoshihisa Kurachi

Email: ykurachi{at}pharma2.med.osaka-u.ac.jp

An exciting epoch is starting as we begin to grasp the variety of physiological functions of the protein 14-3-3. Moore & Perez first described 14-3-3 as a brain-enriched protein in 1968. 14-3-3 was subsequently found to represent a family of regulatory proteins which are ubiquitously expressed in eukaryotic tissues (Fu et al. 2000). The unusual name is derived from the fraction number of DEAE-cellulose chromatography and its migration position in starch-gel electrophoresis. Today 14-3-3 is regarded as a multifunctional protein, like calmodulin, which binds to a variety of cellular proteins and modulates their function. Biochemical and molecular biological techniques have revealed that more than 50 signalling molecules can be regulated by 14-3-3. Through interaction with its effectors, 14-3-3 is now considered to play a pivotal role in the regulation of diverse cell signalling pathways, including activation of protein kinases, cell cycle control, neural development and pathogenesis of bacteria and viruses. To date, seven mammalian 14-3-3 isoforms have been found and these are distinguished by the Greek letters , , , , , and . The structural basis of the specific interaction between a 14-3-3 protein and its target peptide has been elucidated (Yaffe et al. 1997), but the physiological significance of 14-3-3 in mammalian cells has remained elusive.

This year a number of reports on the possible physiological functions of 14-3-3 in mammalian tissues have appeared. Both Niu et al. (2002) and Benzing et al. (2002) revealed that 14-3-3 controls the function of protein 'regulators of G protein signalling' (RGS). RGS proteins are a family of proteins which accelerate the GTPase activity of trimeric G_i or G_q protein subunits and thus act as a negative regulator for a number of G protein signalling pathways. If RGS proteins were active unrestrictedly, they would completely suppress G protein-mediated signalling pathways. This is seen in experiments with the over-expression of RGS proteins. Niu et al. (2002) and Benzing et al. (2002) both showed that 14-3-3 binds to and inactivates RGS proteins and that it therefore acts as a physiological regulator of the G protein cycle. Kagan et al. (2002) recently showed that 14-3-3 modulates ion channel function. 14-3-3 bound to N- and C-termini of the HERG-K⁺ channel and stabilized PKA-mediated phosphorylation, which potentiated the effects of cAMP/PKA. This study was of importance because it was the first to show an interaction between 14-3-3 and an ion channel, though in this case the mode of action of 14-3-3 was conventional as a modulator of kinase activity.

The study by Rajan et al. (2002) in this issue of The Journal of Physiology, on the other hand, provides a novel protocol whereby 14-3-3 plays an essential role in the control of membrane localisation of ion channels. They showed that the 14-3-3 protein is required for surface localisation and functional expression of the two-pore K⁺ channels TASK-1 and TASK-3 in Xenopus oocytes and HEK293 cells, by interacting with their conserved C-terminal domains. Moreover, they showed that 14-3-3 and TASK-1 or -3 could be co-immunoprecipitated from synaptic protein extracts, suggesting their in vivo coupling in native brain tissues. This novel role for 14-3-3 in membrane biology is sure to push the area on to the next step.

14-3-3 is a relatively small protein (~30 kDa) with no additional functional domain, and in general the effects of 14-3-3, including activation or deactivation of enzyme activity and conformation changes in target protein structure, seem to result simply from binding. In this case we should then ask how 14-3-3 regulates membrane localisation (Rajan et al. 2002). The control of membrane trafficking and localisation of proteins involves many processes including the intracellular vesicular transport system, actin- or tubulin-based cytoskeleton systems, motor proteins, etc. The mechanism of 14-3-3-mediated regulation of trafficking and localisation of TASK-1 and -3 remains to be identified and further studies are needed to clarify the whole picture of the role of 14-3-3 proteins in the control of membrane excitability.

In addition, we would like to point out that Rajan et al. (2002) show that the putative PDZ-binding motif in the C-terminus of TASK-1 (-SSV) is not responsible for the membrane localisation of the channel. Since first revealed as a key regulator, PDZ (PSD-95, Disk-large, ZO-1) domain-containing anchoring proteins have been at the centre of studies on the localisation of membrane proteins such as ion channels, transporters and receptors (Sheng & Sala, 2001). If a membrane protein possesses a putative PDZ protein-binding motif at its C-terminal end, it has often been assumed to couple with a PDZ protein. Such enthusiasm has helped to identify a number of novel PDZ proteins. Nevertheless, there may have been cases where these attempts have failed, despite extensive searching with molecular biological (e.g. yeast two-hybrid system) or biochemical (e.g. co-immunoprecipitation) methods. Although the failures might be partly due to lack of skill or 'luck', it is now plausible that some putative PDZ-binding C-terminal motifs may be inherently unrelated to PDZ proteins. We are only beginning to understand the profound wisdom of nature in her manner of arranging the localisation of ion channels to support different functions in cellular electrophysiology.

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This Article Abstract Full Text (PDF) All Versions of this Article: 545/1/2    most recent 2002.033886v1 Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Ishii, M. Articles by Kurachi, Y. Search for Related Content PubMed PubMed Citation Articles by Ishii, M. Articles by Kurachi, Y. Related Collections Perspectives