Asp residues of the Glu-Glu-Asp-Asp pore filter contribute to ion permeation and selectivity of the Cav3.2 T-type channel

Park, HyunJee; Park, So‐Jung; Ahn, E. J.; Lee, So‐Young; Seo, Haengsoo; Lee, Jung-Ha

doi:10.1016/j.ceca.2013.06.006

Cited by 8 publications

(4 citation statements)

References 20 publications

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“…In this work, we have found that the T-type channels of the caps − lpH + neurons are strongly inhibited by acidification as previously established for the T-type channels in heterologous systems (Delisle and Satin, 2000 ; Talavera et al, 2003 ; Park et al, 2013 ). In normal conditions when pH threshold level for AP generation is 6.3, the T-type channels are almost completely inhibited and cannot contribute to the AP generation.…”

Section: Discussionsupporting

confidence: 82%

“…Previously, it was established that the inflammation causes a local acidosis at a site of inflammation (Edlow and Sheldon, 1971 ; Simmen et al, 1994 ; Naghavi et al, 2002 ; Schomack and Gillies, 2003 ). We hypothesized that the excitability of caps − lpH + neurons would change under extracellular acidosis because T-type channels activation properties were found to depend on the pH of extracellular solution (Delisle and Satin, 2000 ; Talavera et al, 2003 ; Park et al, 2013 ). So, we checked if a decrease of pH of extracellular solution changed excitability of the caps − lpH + DRG neurons under normal conditions ( Figure 6 ).…”

Section: Resultsmentioning

confidence: 99%

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Peripheral Inflammation Results in Increased Excitability of Capsaicin-Insensitive Nociceptive DRG Neurons Mediated by Upregulation of ASICs and Voltage-Gated Ion Channels

Duzhyy

Voitenko

Belan

2021

Front. Cell. Neurosci.

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Previously, we have characterized the capsaicin-insensitive low pH-sensitive (caps−lpH+) subtype of small-sized nociceptive dorsal root ganglion (DRG) neurons that express acid-sensing ion channels, T-type Ca2+ channels, and have isolectin B4-negative phenotype. These neurons demonstrated increased excitability in a model of long-term diabetes, contributing to chronic pain sensation. Here we studied changes in the excitability of the caps−lpH+ neurons and underlying changes in the functional expression and gating properties of ion channels under complete Freund's adjuvant (CFA)-induced peripheral inflammation. We have found that, under these pathological conditions, the functional expression of the acid-sensing ion channels (ASICs) and voltage-gated Na+ channels, was increased. In addition, T-type Ca2+ current was significantly increased in the neurons at the membrane potentials close to its resting value. Altogether, the observed changes in the channel functioning shifted a pH level evoking an action potential (AP) toward its physiological value and led to an increase of evoked and spontaneous excitability of the caps−lpH+ neurons that may contribute to hyperalgesia and chronic inflammatory pain.

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Section: Discussionsupporting

confidence: 82%

Section: Resultsmentioning

confidence: 99%

Peripheral Inflammation Results in Increased Excitability of Capsaicin-Insensitive Nociceptive DRG Neurons Mediated by Upregulation of ASICs and Voltage-Gated Ion Channels

Duzhyy

Voitenko

Belan

2021

Front. Cell. Neurosci.

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“…In terms of current kinetics, Ca- α 1T is more similar to mammalian Ca v 3.1 and Ca v 3.2 than Ca v 3.3, which exhibits considerably slower kinetics. In terms of both its relative permeability to Ba 2+ over Ca 2+ and its sensitivity to nickel inhibition, Ca- α 1T is most similar to Ca v 3.2 22 23 .…”

Section: Discussionmentioning

confidence: 99%

Ca-α1T, a fly T-type Ca2+ channel, negatively modulates sleep

Jeong

Lee

Seo

et al. 2015

Sci Rep

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Mammalian T-type Ca2+ channels are encoded by three separate genes (Cav3.1, 3.2, 3.3). These channels are reported to be sleep stabilizers important in the generation of the delta rhythms of deep sleep, but controversy remains. The identification of precise physiological functions for the T-type channels has been hindered, at least in part, by the potential for compensation between the products of these three genes and a lack of specific pharmacological inhibitors. Invertebrates have only one T-type channel gene, but its functions are even less well-studied. We cloned Ca-α1T, the only Cav3 channel gene in Drosophila melanogaster, expressed it in Xenopus oocytes and HEK-293 cells, and confirmed it passes typical T-type currents. Voltage-clamp analysis revealed the biophysical properties of Ca-α1T show mixed similarity, sometimes falling closer to Cav3.1, sometimes to Cav3.2, and sometimes to Cav3.3. We found Ca-α1T is broadly expressed across the adult fly brain in a pattern vaguely reminiscent of mammalian T-type channels. In addition, flies lacking Ca-α1T show an abnormal increase in sleep duration most pronounced during subjective day under continuous dark conditions despite normal oscillations of the circadian clock. Thus, our study suggests invertebrate T-type Ca2+ channels promote wakefulness rather than stabilizing sleep.

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“…However, such examples are not known. Engineering the Ca v 1-like EEEE HFS site onto T-type channels generates T-type channels that are even more sodium permeable, not more calcium selective as would be expected if the HFS site were a principal determinant for ion selectivity in Ca v 3 T-type channels (Talavera et al, 2001 , 2003 ; Park et al, 2013 ).…”

Section: The Hfs Site Is Not the Only Determinant In Governing Ion Sementioning

confidence: 99%

Selectivity filters and cysteine-rich extracellular loops in voltage-gated sodium, calcium, and NALCN channels

et al. 2015

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How nature discriminates sodium from calcium ions in eukaryotic channels has been difficult to resolve because they contain four homologous, but markedly different repeat domains. We glean clues from analyzing the changing pore region in sodium, calcium and NALCN channels, from single-cell eukaryotes to mammals. Alternative splicing in invertebrate homologs provides insights into different structural features underlying calcium and sodium selectivity. NALCN generates alternative ion selectivity with splicing that changes the high field strength (HFS) site at the narrowest level of the hourglass shaped pore where the selectivity filter is located. Alternative splicing creates NALCN isoforms, in which the HFS site has a ring of glutamates contributed by all four repeat domains (EEEE), or three glutamates and a lysine residue in the third (EEKE) or second (EKEE) position. Alternative splicing provides sodium and/or calcium selectivity in T-type channels with extracellular loops between S5 and P-helices (S5P) of different lengths that contain three or five cysteines. All eukaryotic channels have a set of eight core cysteines in extracellular regions, but the T-type channels have an infusion of 4–12 extra cysteines in extracellular regions. The pattern of conservation suggests a possible pairing of long loops in Domains I and III, which are bridged with core cysteines in NALCN, Cav, and Nav channels, and pairing of shorter loops in Domains II and IV in T-type channel through disulfide bonds involving T-type specific cysteines. Extracellular turrets of increasing lengths in potassium channels (Kir2.2, hERG, and K2P1) contribute to a changing landscape above the pore selectivity filter that can limit drug access and serve as an ion pre-filter before ions reach the pore selectivity filter below. Pairing of extended loops likely contributes to the large extracellular appendage as seen in single particle electron cryo-microscopy images of the eel Nav1 channel.

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Asp residues of the Glu-Glu-Asp-Asp pore filter contribute to ion permeation and selectivity of the Cav3.2 T-type channel

Cited by 8 publications

References 20 publications

Peripheral Inflammation Results in Increased Excitability of Capsaicin-Insensitive Nociceptive DRG Neurons Mediated by Upregulation of ASICs and Voltage-Gated Ion Channels

Peripheral Inflammation Results in Increased Excitability of Capsaicin-Insensitive Nociceptive DRG Neurons Mediated by Upregulation of ASICs and Voltage-Gated Ion Channels

Ca-α1T, a fly T-type Ca2+ channel, negatively modulates sleep

Selectivity filters and cysteine-rich extracellular loops in voltage-gated sodium, calcium, and NALCN channels

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