Endoplasmic reticulum potassium-hydrogen exchanger and small conductance calcium-activated potassium channel activities are essential for ER calcium uptake in neurons and cardiomyocytes

J Cell Sci. 2012 Feb 1;125(Pt 3):625-33. doi: 10.1242/jcs.090126. Epub 2012 Feb 13.


Calcium pumping into the endoplasmic reticulum (ER) lumen is thought to be coupled to a countertransport of protons through sarcoplasmic/endoplasmic reticulum calcium ATPase (SERCA) and the members of the ClC family of chloride channels. However, pH in the ER lumen remains neutral, which suggests a mechanism responsible for proton re-entry. We studied whether cation-proton exchangers could act as routes for such a re-entry. ER Ca(2+) uptake was measured in permeabilized immortalized hypothalamic neurons, primary rat cortical neurons and mouse cardiac fibers. Replacement of K(+) in the uptake solution with Na(+) or tetraethylammonium led to a strong inhibition of Ca(2+) uptake in neurons and cardiomyocytes. Furthermore, inhibitors of the potassium-proton exchanger (quinine or propranolol) but not of the sodium-proton exchanger reduced ER Ca(2+) uptake by 56-82%. Externally added nigericin, a potassium-proton exchanger, attenuated the inhibitory effect of propranolol. Inhibitors of small conductance calcium-sensitive K(+) (SK(Ca)) channels (UCL 1684, dequalinium) blocked the uptake of Ca(2+) by the ER in all preparations by 48-94%, whereas inhibitors of other K(+) channels (IK(Ca), BK(Ca) and K(ATP)) had no effect. Fluorescence microscopy and western blot analysis revealed the presence of both SK(Ca) channels and the potassium-proton exchanger leucine zipper-EF-hand-containing transmembrane protein 1 (LETM1) in ER in situ and in the purified ER fraction. The data obtained demonstrate that SK(Ca) channels and LETM1 reside in the ER membrane and that their activity is essential for ER Ca(2+) uptake.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Calcium / metabolism
  • Cells, Cultured
  • Endoplasmic Reticulum / metabolism*
  • Ion Transport / drug effects
  • Mice
  • Models, Biological
  • Myocytes, Cardiac / drug effects
  • Myocytes, Cardiac / metabolism*
  • Neurons / drug effects
  • Neurons / metabolism*
  • Nigericin / pharmacology
  • Potassium-Hydrogen Antiporters / antagonists & inhibitors
  • Potassium-Hydrogen Antiporters / metabolism*
  • Propranolol / pharmacology
  • Rats
  • Small-Conductance Calcium-Activated Potassium Channels / antagonists & inhibitors
  • Small-Conductance Calcium-Activated Potassium Channels / metabolism*


  • Potassium-Hydrogen Antiporters
  • Small-Conductance Calcium-Activated Potassium Channels
  • Propranolol
  • Nigericin
  • Calcium