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• W2027271646 abstract "Tight regulation of calcium entry through the L-type calcium channel CaV1.2 ensures optimal excitation-response coupling. In this issue of Neuron, Michailidis et al., 2014Michailidis I.E. Abele-Henckels K. Zhang W.K. Lin B. Yu Y. Geyman L.S. Ehlers M.D. Pnevmatikakis E.A. Yang J. Neuron. 2014; 82 (this issue): 1045-1057Abstract Full Text Full Text PDF PubMed Scopus (28) Google Scholar demonstrate that CaV1.2 activity triggers negative feedback regulation through proteolytic cleavage of the channel within the core of the pore-forming subunit. Tight regulation of calcium entry through the L-type calcium channel CaV1.2 ensures optimal excitation-response coupling. In this issue of Neuron, Michailidis et al., 2014Michailidis I.E. Abele-Henckels K. Zhang W.K. Lin B. Yu Y. Geyman L.S. Ehlers M.D. Pnevmatikakis E.A. Yang J. Neuron. 2014; 82 (this issue): 1045-1057Abstract Full Text Full Text PDF PubMed Scopus (28) Google Scholar demonstrate that CaV1.2 activity triggers negative feedback regulation through proteolytic cleavage of the channel within the core of the pore-forming subunit. The L-type calcium channel CaV1.2 is an integral cell membrane protein complex that contributes to the influx of calcium into excitable cells. This influx occurs in response to membrane depolarization and can trigger a wide range of cellular processes, including cardiac muscle contraction, endocrine hormone secretion, and neuronal gene expression (Catterall, 2000Catterall W.A. Annu. Rev. Cell Dev. Biol. 2000; 16: 521-555Crossref PubMed Scopus (1945) Google Scholar, Simms and Zamponi, 2014Simms B.A. Zamponi G.W. Neuron. 2014; 82: 24-45Abstract Full Text Full Text PDF PubMed Scopus (410) Google Scholar, Wheeler et al., 2012Wheeler D.G. Groth R.D. Ma H. Barrett C.F. Owen S.F. Safa P. Tsien R.W. Cell. 2012; 149: 1112-1124Abstract Full Text Full Text PDF PubMed Scopus (206) Google Scholar). These examples of excitation-response coupling depend critically on a cell’s ability to maintain precise control over intracellular calcium levels. Therefore, it is not surprising that an arsenal of sophisticated mechanisms exist to regulate calcium channel activity itself. Indeed, feedback control over the entry of calcium through voltage-dependent calcium channels occurs through the regulation of channel activity, expression, and trafficking to and from the plasma membrane. These disparate modes of regulation may be arrayed to provide negative feedback over multiple timescales. For example, in response to brief depolarization, calcium entry via L-type channels activates calmodulin that is already prebound to the channel. This starts rapid, calcium-dependent inactivation of the channel within milliseconds (Peterson et al., 1999Peterson B.Z. DeMaria C.D. Adelman J.P. Yue D.T. Neuron. 1999; 22: 549-558Abstract Full Text Full Text PDF PubMed Scopus (714) Google Scholar, Zühlke et al., 1999Zühlke R.D. Pitt G.S. Deisseroth K. Tsien R.W. Reuter H. Nature. 1999; 399: 159-162Crossref PubMed Scopus (738) Google Scholar), curtailing calcium entry while the membrane remains depolarized. On the other hand, prolonged depolarization results in the removal of CaV1.2 channels from the membrane, restraining calcium entry over a much slower timescale (Green et al., 2007Green E.M. Barrett C.F. Bultynck G. Shamah S.M. Dolmetsch R.E. Neuron. 2007; 55: 615-632Abstract Full Text Full Text PDF PubMed Scopus (74) Google Scholar). In their provocative study featured in this issue of Neuron, Michailidis, Yang, and colleagues (2014) provide evidence for yet another form of activity-dependent feedback inhibition of voltage-dependent calcium channels: calcium-dependent proteolysis of the main body of the CaV1.2 channel. The concept of triggering negative feedback regulation of the CaV1.2 channel through proteolytic processing is not unique in itself. Indeed, Hulme et al., 2006Hulme J.T. Yarov-Yarovoy V. Lin T.W. Scheuer T. Catterall W.A. J. Physiol. 2006; 576: 87-102Crossref PubMed Scopus (142) Google Scholar found that proteolysis of the C-terminal domain of the CaV1.2 channel produces a noncovalently associated and potent autoinhibitory domain. Michailidis et al., 2014Michailidis I.E. Abele-Henckels K. Zhang W.K. Lin B. Yu Y. Geyman L.S. Ehlers M.D. Pnevmatikakis E.A. Yang J. Neuron. 2014; 82 (this issue): 1045-1057Abstract Full Text Full Text PDF PubMed Scopus (28) Google Scholar have uncovered an equally striking example of CaV1.2 proteolytic processing; channel activity-dependent cleavage within the core of the CaV1.2 pore-forming subunit. This midchannel proteolysis generates fragments in the plasma membrane that do not form functional channels on their own but that seem to display distinct biophysical properties when paired with a complementary fragment. In this study, Michailidis et al., 2014Michailidis I.E. Abele-Henckels K. Zhang W.K. Lin B. Yu Y. Geyman L.S. Ehlers M.D. Pnevmatikakis E.A. Yang J. Neuron. 2014; 82 (this issue): 1045-1057Abstract Full Text Full Text PDF PubMed Scopus (28) Google Scholar biotinylated surface channels and performed western blots using antibodies directed against distinct regions of the CaV1.2 channel. In so doing, they identified the full-length channel (240 kDa) and a prominent fragment that contains part of the II-III loop, repeats III and IV, and the C terminus (150 kDa). A complementary N-terminal fragment (90 kDa), including the N terminus and repeats I and II, was also evident. Michailidis et al., 2014Michailidis I.E. Abele-Henckels K. Zhang W.K. Lin B. Yu Y. Geyman L.S. Ehlers M.D. Pnevmatikakis E.A. Yang J. Neuron. 2014; 82 (this issue): 1045-1057Abstract Full Text Full Text PDF PubMed Scopus (28) Google Scholar went on to show that the cleavage of the full-length channel was the handiwork of calcium-dependent processes—in part, the protease calpain—and could be bidirectionally manipulated. They also found evidence for involvement of PEST sequences, which serve as signals for rapid proteolytic degradation through the cell quality control system (Rechsteiner and Rogers, 1996Rechsteiner M. Rogers S.W. Trends Biochem. Sci. 1996; 21: 267-271Abstract Full Text PDF PubMed Scopus (1404) Google Scholar). PEST-mediated protein degradation plays a major role in modulating neuronal calcium channel function through regulation of the Cavα1 subunit (Catalucci et al., 2009Catalucci D. Zhang D.H. DeSantiago J. Aimond F. Barbara G. Chemin J. Bonci D. Picht E. Rusconi F. Dalton N.D. et al.J. Cell Biol. 2009; 184: 923-933Crossref PubMed Scopus (90) Google Scholar) and the Cavβ3 accessory subunit (Sandoval et al., 2006Sandoval A. Oviedo N. Tadmouri A. Avila T. De Waard M. Felix R. Eur. J. Neurosci. 2006; 23: 2311-2320Crossref PubMed Scopus (20) Google Scholar). Whatever the detailed mechanism, midbody regulation is intriguing for multiple reasons. It enzymatically severs the tandem linkage of four individual motifs—each with Shaker K channel-like structure—a hallmark feature of calcium and sodium channels that took eons to evolve; this is a more radical change in VGCC architecture than abbreviation of the long C-terminal tail. The midchannel cleavage appears to leave two pieces that can remain together in a partially functional state, based on evidence from engineered complementary fragments. Resulting current intensities, at levels <40% of those generated by intact pore-forming subunits, were consistently found regardless of where the split was imposed. Thus, the cleaved channel appears to lie somewhere between fully functional and nonfunctional, a convenient step down for autoregulation of calcium influx. Biotinylation of intact tissue allowed Michailidis et al., 2014Michailidis I.E. Abele-Henckels K. Zhang W.K. Lin B. Yu Y. Geyman L.S. Ehlers M.D. Pnevmatikakis E.A. Yang J. Neuron. 2014; 82 (this issue): 1045-1057Abstract Full Text Full Text PDF PubMed Scopus (28) Google Scholar to focus on proteins unambiguously localized to the surface membrane. In a complementary prelabeling approach, they tackled the question of whether the CaV1.2 fragments always cling tightly to each other or sometimes drift away. After prelabeling the N-terminal fragment with a green cytoplasmic GFP tag, and the C-terminal fragment with an HA-epitope tag later immunostained in red, they checked whether red and green intensities had identical spatial distributions across the surface of the cell. If no cleavage took place, the red C-terminal and green N-terminal fragments would remain perfectly matched up (or would at least be equally abundant within the limits of optical analysis; pixel width, 0.2 μm) and their noncolocalization index (NCI = red/green ratio) would be unity throughout (Figure 1). Instead, the red/green ratio varied widely from unity over the surface of cultured neurons, resembling a patchwork quilt of yellow, red, and green. This provided Michailidis et al., 2014Michailidis I.E. Abele-Henckels K. Zhang W.K. Lin B. Yu Y. Geyman L.S. Ehlers M.D. Pnevmatikakis E.A. Yang J. Neuron. 2014; 82 (this issue): 1045-1057Abstract Full Text Full Text PDF PubMed Scopus (28) Google Scholar with cell biological evidence for the existence of midbody cleavage but also raised new questions about what pulls the N- and C-terminal fragments apart, and what their ultimate functions might be. As it stands, the evidence suggests that neurons display a dispersion of VGCC molecules in different states, reflecting the neuron’s previous history of activity: full-length subunits, fragments that might modulate full-length subunits, paired-up fragments, and even isolated clusters of C-terminal fragments. The array of CaV1.2 components may even vary dramatically with age. Preview authors have the privilege of blithely advocating for future experiments. We think that it will be important to study the kinetics of the midbody cleavage and the cell biology of fragment anchoring and turnover. We note that differential regulation of internalization rather than regulation of cleavage itself would also show up as a calcium-dependent shift in the relative surface abundance of full-length and C-terminal fragments that could account for reduced channel current density. It would also be worthwhile to determine whether midbody cleavage is generalizable to other kinds of VGCC’s, as the preliminary findings of Michailidis et al., 2014Michailidis I.E. Abele-Henckels K. Zhang W.K. Lin B. Yu Y. Geyman L.S. Ehlers M.D. Pnevmatikakis E.A. Yang J. Neuron. 2014; 82 (this issue): 1045-1057Abstract Full Text Full Text PDF PubMed Scopus (28) Google Scholar with CaV2.1 would suggest. Finally, it would be interesting to test whether the isolated C-terminal fragments physiologically modulate full-length channel subunits or serve a unique neuronal function of their own. Our hunch is that they are not just proteinaceous detritus merely awaiting removal for further proteolysis. Might they serve as membrane anchors for ancillary proteins even when their usefulness as flux-generating devices is over? Many cytoplasmic proteins interact with the CaV1.2 C-terminal tail. Could they act as pore-less voltage sensors since they still contain structural components for sensing voltage? Voltage-dependent conformational changes may serve a signaling role in neurons (M.R. Tadross et al., 2013, SFN, abstract), by analogy to the function of CaV1.1, the classical voltage sensor of skeletal muscle. Gating current measurements would indicate whether conformational changes are intact in isolated C-terminal fragments and in complementary fragment pairs, both for generation of gated calcium flux, and for conveying information about neuronal depolarization per se. The voltage-dependent gating of fragment pairs is significantly different from the full-length channel, raising the possibility that gating conformational changes are somehow different. In conclusion, Michailidis et al., 2014Michailidis I.E. Abele-Henckels K. Zhang W.K. Lin B. Yu Y. Geyman L.S. Ehlers M.D. Pnevmatikakis E.A. Yang J. Neuron. 2014; 82 (this issue): 1045-1057Abstract Full Text Full Text PDF PubMed Scopus (28) Google Scholar have added both potency and complexity to our picture of how calcium channel activity, so important for cellular homeostasis, is itself regulated. R.D.G., N.N.T., and R.W.T. have been supported by NIGMS (GM058234) and NIMH (MH071739). Age-Related Homeostatic Midchannel Proteolysis of Neuronal L-type Voltage-Gated Ca2+ ChannelsMichailidis et al.NeuronJune 04, 2014In BriefMichailidis et al. show that the core of the pore-forming Cav1.2 subunit of neuronal L-type voltage-gated calcium channels is proteolytically cleaved, resulting in Cav1.2 fragment channels that separate on the plasma membrane. This “midchannel” proteolysis is regulated by activity and increases with age. Full-Text PDF Open Archive" @default.
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• W2027271646 title "CaV1.2 Calcium Channels: Just Cut Out to Be Regulated?" @default.
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