The C Terminus of the L-Type Voltage-Gated Calcium Channel CaV1.2 Encodes a Transcription Factor

Gomez‐Ospina, Natalia; Tsuruta, Fuminori; Chang, Odmara L. Barreto; Hu, Linda; Dolmetsch, Ricardo

doi:10.1016/j.cell.2006.10.017

Cited by 354 publications

(375 citation statements)

References 44 publications

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“…Kubodera et al (29) also reported the production of similar fragment in HEK293T cells overexpressing Ca V 2.1. Interestingly, the C terminus of the L-type Ca V 1.2 Ca 2ϩ channel can also be cleaved and translocate to the nucleus, where it may act as a transcription factor (30). In our Sca6 KI mice, we could not detect such a small C-terminal fragment in cerebellar extracts.…”

Section: Discussioncontrasting

confidence: 39%

Spinocerebellar ataxia type 6 knockin mice develop a progressive neuronal dysfunction with age-dependent accumulation of mutant Ca _V 2.1 channels

Watase

Barrett²,

Miyazaki³

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

157

164

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Spinocerebellar ataxia type 6 (SCA6) is a neurodegenerative disorder caused by CAG repeat expansions within the voltage-gated calcium (CaV) 2.1 channel gene. It remains controversial whether the mutation exerts neurotoxicity by changing the function of CaV2.1 channel or through a gain-of-function mechanism associated with accumulation of the expanded polyglutamine protein.We generated three strains of knockin (KI) mice carrying normal, expanded, or hyperexpanded CAG repeat tracts in the Cacna1a locus. The mice expressing hyperexpanded polyglutamine (Sca6 84Q ) developed progressive motor impairment and aggregation of mutant CaV2.1 channels. Electrophysiological analysis of cerebellar Purkinje cells revealed similar Ca 2؉ channel current density among the three KI models. Neither voltage sensitivity of activation nor inactivation was altered in the Sca6 84Q neurons, suggesting that expanded CAG repeat per se does not affect the intrinsic electrophysiological properties of the channels. The pathogenesis of SCA6 is apparently linked to an age-dependent process accompanied by accumulation of mutant CaV2.1 channels.cerebullum ͉ polyglutamine ͉ P/Q-type voltage-dependent calcium channel

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Section: Discussioncontrasting

confidence: 39%

Spinocerebellar ataxia type 6 knockin mice develop a progressive neuronal dysfunction with age-dependent accumulation of mutant Ca _V 2.1 channels

Watase

Barrett²,

Miyazaki³

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

157

164

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“…It has been reported that an L-type voltage-gated Ca 2 þ channel is proteolytically cleaved to form a C-terminal fragment, which is translocated into the nucleus and alters the endogenous transcription of a wide variety of genes. 21 However, the molecular mechanisms that mediate this change in functionality in the TRPM2 protein between cancerous and non-cancerous tissues remain elusive. The difference in the subcellular locations of TRPM2 between cancerous and non-cancerous prostate cells may explain the switching of these two roles.…”

Section: Discussionmentioning

confidence: 99%

Novel role for the transient receptor potential channel TRPM2 in prostate cancer cell proliferation

Zeng

Sikka

Huang

et al. 2009

Prostate Cancer Prostatic Dis

117

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We have identified a novel function for a member of the transient receptor potential (TRP) protein super-family, TRPM2, in prostate cancer cell proliferation. TRPM2 encodes a non-selective cationpermeable ion channel. We found that selectively knocking down TRPM2 with the small interfering RNA technique inhibited the growth of prostate cancer cells but not of non-cancerous cells. The subcellular localization of this protein is also remarkably different between cancerous and non-cancerous cells. In BPH-1 (benign), TRPM2 protein is homogenously located near the plasma membrane and in the cytoplasm, whereas in the cancerous cells (PC-3 and DU-145), a significant amount of the TRPM2 protein is located in the nuclei in a clustered pattern. Furthermore, we have found that TRPM2 inhibited nuclear ADP-ribosylation in prostate cancer cells. However, TRPM2 knockdown-induced inhibition of proliferation is independent of the activity of poly(ADP-ribose) polymerases. We conclude that TRPM2 is essential for prostate cancer cell proliferation and may be a potential target for the selective treatment of prostate cancer.

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“…Upon dissociation from the channel, the Asn-Ca v 1.1 fragment migrates to the nucleus and functions as a transcriptional regulator. 97,143,144,145 #7. Arg-GlyT1A is the Ct fragment of the transmembrane GlyT1A glycine transporter.…”

Section: Monitoring Protein Fragments and Reacting To Their Accumulationmentioning

confidence: 99%

Augmented generation of protein fragments during wakefulness as the molecular cause of sleep: a hypothesis

Varshavsky

2012

Protein Science

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Despite extensive understanding of sleep regulation, the molecular-level cause and function of sleep are unknown. I suggest that they originate in individual neurons and stem from increased production of protein fragments during wakefulness. These fragments are transient parts of protein complexes in which the fragments were generated. Neuronal Ca 21 fluxes are higher during wakefulness than during sleep. Subunits of transmembrane channels and other proteins are cleaved by Ca 21 -activated calpains and by other nonprocessive proteases, including caspases and secretases. In the proposed concept, termed the fragment generation (FG) hypothesis, sleep is a state during which the production of fragments is decreased (owing to lower Ca 21 transients) while fragment-destroying pathways are upregulated. These changes facilitate the elimination of fragments and the remodeling of protein complexes in which the fragments resided. The FG hypothesis posits that a proteolytic cleavage, which produces two fragments, can have both deleterious effects and fitness-increasing functions. This (previously not considered) dichotomy can explain both the conservation of cleavage sites in proteins and the evolutionary persistence of sleep, because sleep would counteract deleterious aspects of protein fragments. The FG hypothesis leads to new explanations of sleep phenomena, including a longer sleep after sleep deprivation. Studies in the 1970s showed that ethanol-induced sleep in mice can be strikingly prolonged by intracerebroventricular injections of either Ca 21 alone or Ca 21 and its ionophore (Erickson et al., Science 1978;199:1219-1221 Harris, Pharmacol Biochem Behav 1979;10:527-534; Erickson et al., Pharmacol Biochem Behav 1980;12:651-656). These results, which were never interpreted in connection to protein fragments or the function of sleep, may be accounted for by the FG hypothesis about molecular causation of sleep.

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The C Terminus of the L-Type Voltage-Gated Calcium Channel CaV1.2 Encodes a Transcription Factor

Cited by 354 publications

References 44 publications

Spinocerebellar ataxia type 6 knockin mice develop a progressive neuronal dysfunction with age-dependent accumulation of mutant Ca _V 2.1 channels

Spinocerebellar ataxia type 6 knockin mice develop a progressive neuronal dysfunction with age-dependent accumulation of mutant Ca _V 2.1 channels

Novel role for the transient receptor potential channel TRPM2 in prostate cancer cell proliferation

Augmented generation of protein fragments during wakefulness as the molecular cause of sleep: a hypothesis

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The C Terminus of the L-Type Voltage-Gated Calcium Channel CaV1.2 Encodes a Transcription Factor

Cited by 354 publications

References 44 publications

Spinocerebellar ataxia type 6 knockin mice develop a progressive neuronal dysfunction with age-dependent accumulation of mutant Ca V 2.1 channels

Spinocerebellar ataxia type 6 knockin mice develop a progressive neuronal dysfunction with age-dependent accumulation of mutant Ca V 2.1 channels

Novel role for the transient receptor potential channel TRPM2 in prostate cancer cell proliferation

Augmented generation of protein fragments during wakefulness as the molecular cause of sleep: a hypothesis

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Spinocerebellar ataxia type 6 knockin mice develop a progressive neuronal dysfunction with age-dependent accumulation of mutant Ca _V 2.1 channels

Spinocerebellar ataxia type 6 knockin mice develop a progressive neuronal dysfunction with age-dependent accumulation of mutant Ca _V 2.1 channels