Small conductance Ca 2+-activated K + channels in the plasma membrane, mitochondria and the ER: Pharmacology and implications in neuronal diseases

Neurochem Int. 2017 Oct;109:13-23. doi: 10.1016/j.neuint.2017.05.005. Epub 2017 May 13.

Abstract

Ca2+-activated K+ (KCa) channels regulate after-hyperpolarization in many types of neurons in the central and peripheral nervous system. Small conductance Ca2+-activated K+ (KCa2/SK) channels, a subfamily of KCa channels, are widely expressed in the nervous system, and in the cardiovascular system. Voltage-independent SK channels are activated by alterations in intracellular Ca2+ ([Ca2+]i) which facilitates the opening of these channels through binding of Ca2+ to calmodulin that is constitutively bound to the SK2 C-terminus. In neurons, SK channels regulate synaptic plasticity and [Ca2+]i homeostasis, and a number of recent studies elaborated on the emerging neuroprotective potential of SK channel activation in conditions of excitotoxicity and cerebral ischemia, as well as endoplasmic reticulum (ER) stress and oxidative cell death. Recently, SK channels were discovered in the inner mitochondrial membrane and in the membrane of the endoplasmic reticulum which sheds new light on the underlying molecular mechanisms and pathways involved in SK channel-mediated protective effects. In this review, we will discuss the protective properties of pharmacological SK channel modulation with particular emphasis on intracellularly located SK channels as potential therapeutic targets in paradigms of neuronal dysfunction.

Keywords: Cell death; Mitochondria; Neuroprotection; SK channels.

Publication types

  • Review

MeSH terms

  • Animals
  • Carbamates / pharmacology
  • Carbamates / therapeutic use
  • Cell Membrane / drug effects
  • Cell Membrane / metabolism*
  • Endoplasmic Reticulum / drug effects
  • Endoplasmic Reticulum / metabolism*
  • Humans
  • Mitochondria / drug effects
  • Mitochondria / metabolism*
  • Nervous System Diseases / drug therapy
  • Nervous System Diseases / metabolism*
  • Neurons / drug effects
  • Neurons / metabolism
  • Piperidines / pharmacology
  • Piperidines / therapeutic use
  • Potassium Channels, Calcium-Activated / agonists
  • Potassium Channels, Calcium-Activated / antagonists & inhibitors
  • Potassium Channels, Calcium-Activated / metabolism*

Substances

  • 4-(2-methoxyphenylcarbamoyloxymethyl)piperidine-1-carboxylic acid tert-butyl ester
  • Carbamates
  • Piperidines
  • Potassium Channels, Calcium-Activated