Kinetics of internalization and degradation of N-type voltage-gated calcium channels: Role of the α2/δ subunit

Bernstein, Geula M.; Jones, Owen

doi:10.1016/j.ceca.2006.04.010

Cited by 64 publications

(54 citation statements)

References 65 publications

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“…Previously, a stabilizing effect of TRPV1 on the membrane expression of TRPA1 was suggested . Internalization of membrane-bound channels can be suppressed by interactions with other proteins including subunits of the channels (Bernstein and Jones, 2007), and functional TRPV1 tetramers can be modulated by cAMP-dependent translocation of TRPV1 monomers from intracellular pools to the cell membrane (Vetter et al, 2008). Again, since neither the affinity nor the number of TRPV1 binding sites changed during TRPA1 activation, our experiments indicate that TRPV1 was not internalized or recruited to the cell membrane from intracellular pools.…”

Section: Discussionmentioning

confidence: 74%

Modulation of Transient Receptor Vanilloid 1 Activity by Transient Receptor Potential Ankyrin 1

2013

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Transient receptor potential vanilloid 1 (TRPV1) is a nonselective ligand-gated cation channel responding to noxious heat, protons, and chemicals such as capsaicin. TRPV1 is expressed in sensory neurons and plays a critical role in pain associated with tissue injury, inflammation, and nerve lesions. Transient receptor potential ankyrin 1 (TRPA1) is coexpressed with TRPV1. It is activated by compounds that cause a burning sensation (e.g., mustard oil) and, indirectly, by components of the inflammatory milieu eliciting nociceptor excitation and pain hypersensitivity. Previous studies indicate an interaction of TRPV1 and TRPA1 signaling pathways. Here we sought to examine the molecular mechanisms underlying such interactions in nociceptive neurons. We first excluded physical interactions of both channels using radioligand binding studies. By microfluorimetry, electrophysiological experiments, cAMP measurements, and site-directed mutagenesis we found a sensitization of TRPV1 after TRPA1 stimulation with mustard oil in a calcium and cAMP/protein kinase A (PKA)-dependent manner. TRPA1 stimulation enhanced TRPV1 phosphorylation via the putative PKA phosphorylation site serine 116. We also detected calcium-sensitive increased TRPV1 activity after TRPA1 activation in dorsal root ganglion neurons. The inhibition of TRPA1 by HC-030031 (1,2,3,6-tetrahydro-1,3-dimethyl-N-[4-(1-methylethyl)phenyl]-2,6-dioxo-7H-purine-7-acetamide, 2-(1,3-dimethyl-2,6-dioxo-1,2,3,6-tetrahydro-7H-purin-7-yl)-N-(4-isopropylphenyl)acetamide) after its initial stimulation (and the calcium-insensitive TRPA1 mutant D477A) still showed increased capsaicin-induced TRPV1 activity. This excludes a calcium-induced additive TRPA1 current after TRPV1 stimulation. Our study shows sensitization of TRPV1 via activation of TRPA1, which involves adenylyl cyclase, increased cAMP, subsequent translocation and activation of PKA, and phosphorylation of TRPV1 at PKA phosphorylation residues. This suggests that cross-sensitization of TRP channels contributes to enhanced pain sensitivity in inflamed tissues.

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Section: Discussionmentioning

confidence: 74%

Modulation of Transient Receptor Vanilloid 1 Activity by Transient Receptor Potential Ankyrin 1

2013

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“…Because synaptic Ca 2ϩ currents in salamander photoreceptors are strongly inhibited by arachidonic acid (62), it will be of interest to determine whether ␤ 2X13 alters the sensitivity of Ca v 1.4 channels to this arachidonic acid or other neuromodulators. (63,64). These effects are due in part to a von Willebrand factor A (VFA) domain and in particular a metal ion adhesion motif (MIDAS), the mutation of which prevents the cell surface trafficking function of ␣ 2 ␦ 2 on Ca v 2.1 currents (64).…”

Section: Discussionmentioning

confidence: 99%

Characterization of Cav1.4 Complexes (α11.4, β2, and α2δ4) in HEK293T Cells and in the Retina

Lee

Wang

Williams

et al. 2015

Journal of Biological Chemistry

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“…However, calcium channels also contain ␣ 2 ␦ and ␤ subunits that can have a substantial influence on the properties of calcium channels when expressed in heterologous systems (Arikkath and Campbell, 2003). Both ␣ 2 ␦ and ␤ subunits can markedly increase surface expression of the channels Wiser et al, 1996;Bichet et al, 2000;Felix, 2005) and can also influence the gating properties of the channel (Arikkath and Campbell, 2003;Bernstein and Jones, 2007). The ␤ subunit is entirely intracellular and is the target for several pathways that modulate calcium channel function (Dolphin, 2003).…”

Section: Introductionmentioning

confidence: 99%

Mutations in aDrosophilaα₂δ Voltage-Gated Calcium Channel Subunit Reveal a Crucial Synaptic Function

Dickman¹,

Kurshan²,

Schwarz³

2008

J. Neurosci.

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Voltage-dependent calcium channels regulate many aspects of neuronal biology, including synaptic transmission. In addition to their ␣ 1 subunit, which encodes the essential voltage gate and selective pore, calcium channels also contain auxiliary ␣ 2 ␦, ␤, and ␥ subunits. Despite progress in understanding the biophysical properties of calcium channels, the in vivo functions of these auxiliary subunits remain unclear. We have isolated mutations in the gene encoding an ␣ 2 ␦ calcium channel subunit (d␣ 2 ␦-3) using a forward genetic screen in Drosophila. Null mutations in this gene are embryonic lethal and can be rescued by expression in the nervous system, demonstrating that the essential function of this subunit is neuronal. The photoreceptor phenotype of d␣ 2 ␦-3 mutants resembles that of the calcium channel ␣ 1 mutant cacophony (cac), suggesting shared functions. We have examined in detail genotypes that survive to the third-instar stage. Electrophysiological recordings demonstrate that synaptic transmission is severely impaired in these mutants. Thus the ␣ 2 ␦ calcium channel subunit is critical for calcium-dependent synaptic function. As such, this Drosophila isoform is the likely partner to the presynaptic calcium channel ␣ 1 subunit encoded by the cac locus. Consistent with this hypothesis, cacGFP fluorescence at the neuromuscular junction is reduced in d␣ 2 ␦-3 mutants. This is the first characterization of an ␣ 2 ␦-3 mutant in any organism and indicates a necessary role for ␣ 2 ␦-3 in presynaptic vesicle release and calcium channel expression at active zones.

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Kinetics of internalization and degradation of N-type voltage-gated calcium channels: Role of the α2/δ subunit

Cited by 64 publications

References 65 publications

Modulation of Transient Receptor Vanilloid 1 Activity by Transient Receptor Potential Ankyrin 1

Modulation of Transient Receptor Vanilloid 1 Activity by Transient Receptor Potential Ankyrin 1

Characterization of Cav1.4 Complexes (α11.4, β2, and α2δ4) in HEK293T Cells and in the Retina

Mutations in aDrosophilaα₂δ Voltage-Gated Calcium Channel Subunit Reveal a Crucial Synaptic Function

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Kinetics of internalization and degradation of N-type voltage-gated calcium channels: Role of the α2/δ subunit

Cited by 64 publications

References 65 publications

Modulation of Transient Receptor Vanilloid 1 Activity by Transient Receptor Potential Ankyrin 1

Modulation of Transient Receptor Vanilloid 1 Activity by Transient Receptor Potential Ankyrin 1

Characterization of Cav1.4 Complexes (α11.4, β2, and α2δ4) in HEK293T Cells and in the Retina

Mutations in aDrosophilaα2δ Voltage-Gated Calcium Channel Subunit Reveal a Crucial Synaptic Function

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Resources

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Mutations in aDrosophilaα₂δ Voltage-Gated Calcium Channel Subunit Reveal a Crucial Synaptic Function