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March 24, 2009The Journal of PhysiologyOpen Access

Human ClCa1 modulates anionic conduction of calcium‐dependent chloride currents

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Key result

Heterologous expression of hClCa1 in HEK293 and NCIH522 cells increased the amplitude of Ca(2+)-dependent Cl- currents and Cl- conductance by lowering energy barriers for ion translocation.

Population

HEK293 and NCIH522 cell lines

Comparison

Heterologous expression of human ClCa1 (hClCa1) vs Baseline/constitutive Ca-dependent Cl- currents…

Design

Preclinical

Authors

MHMartine HamannUniversity of LeicesterAGAdele GibsonGlaxoSmithKline (United Kingdom)NDNoel W. DaviesGoogle (United States)

Discussion

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Implication

Findings remain preclinical; challenges hClCa1 channel-forming role and leaves open native tissue validation.

Key Points

  • To determine whether human ClCa1 forms functional calcium-dependent chloride channels directly or regulates preexisting endogenous chloride currents.
  • Expressed human ClCa1 heterologously in HEK293 and NCIH522 cell lines.
  • Conducted whole-cell patch-clamp electrophysiological recordings to quantify calcium-dependent chloride current amplitudes, ionic permeabilities, and conductance ratios.
  • Applied Eyring rate theory using a two-barrier, one-site channel model to simulate the biophysical impact of hClCa1 on ionic pore energetics.
  • HEK293 and NCIH522 cells exhibited constitutive calcium-dependent chloride currents, and hClCa1 expression significantly amplified these current amplitudes without altering the ionic permeability sequence.
  • Expression of hClCa1 increased chloride conductance while reducing the G(SCN-)/G(Cl-) conductance ratio from approximately 2–3 down to approximately 1.
  • Theoretical kinetic modeling demonstrated that hClCa1 increases single-channel conductance by lowering the first and second energy barriers for pore translocation rather than forming channels de novo or increasing membrane trafficking.

Structured PICO

P
Population
HEK293 and NCIH522 cell lines
I
Intervention
Heterologous expression of human ClCa1 (hClCa1)
C
Comparator
Baseline/constitutive Ca(2+)-dependent Cl- currents in the same cell lines
O
Outcome
Amplitude and conductance of Ca(2+)-dependent Cl- currentssurrogate

hClCa1 does not form Ca(2+)-dependent Cl- channels itself but elevates the single channel conductance of endogenous channels by lowering energy barriers for ion translocation.

Cite This Study

Hamann et al. (2009) studied this question. Heterologous expression of hClCa1 vs. Constitutive/endogenous channels was evaluated on Ca(2+)-dependent Cl- currents and conductance. Heterologous expression of hClCa1 in HEK293 and NCIH522 cells increased the amplitude of Ca(2+)-dependent Cl- currents and Cl- conductance by lowering energy barriers for ion translocation.

synapsesocial.com/papers/6a71be81660549caf2c6400chttps://doi.org/10.1113/jphysiol.2009.170159
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Also Consider

Synapse has enriched 5 closely related papers on similar clinical questions. Consider them for comparative context:

  1. 1Ca(2+)-activated Cl- currents are activated by metabolic inhibition in rat pulmonary artery smooth muscle cells1997 · 38 citations
  2. 2A rate theory model for Mg2+ block of ATP‐dependent potassium channels of rat skeletal muscle.1996 · 12 citations
  3. 3The Large Conductance Potassium Channel β-Subunit Can Interact with and Modulate the Functional Properties of a Calcium-activated Chloride Channel, CLCA12002 · 41 citations
  4. 4Comparison of the properties of CLCA1 generated currents and ICl(Ca) in murine portal vein smooth muscle cells2002 · 56 citations
  5. 5pCLCA1 lacks inherent chloride channel activity in an epithelial colon carcinoma cell line2004 · 35 citations