Modulators of small- and intermediate-conductance calcium-activated potassium channels and their therapeutic indications

Heike Wulff, Aaron Kolski-Andreaco, Ananthakrishnan Sankaranarayanan, Jean Marc Sabatier, Vikram Shakkottai

Research output: Contribution to journalArticle

149 Citations (Scopus)

Abstract

Calcium-activated potassium channels modulate calcium signaling cascades and membrane potential in both excitable and non-excitable cells. In this article we will review the physiological properties, the structure activity relationships of the existing peptide and small molecule modulators and the therapeutic importance of the three small-conductance channels KCa2.1-KCa2.3 (a.k.a. SK1-SK3) and the intermediate-conductance channel KCa3.1 (a.k.a. IKCal). The apamin-sensitive KCa2 channels contribute to the medium afterhyperpolarization and are crucial regulators of neuronal excitability. Based on behavioral studies with apamin and on observations made in several transgenic mouse models, KCa2 channels have been proposed as targets for the treatment of ataxia, epilepsy, memory disorders and possibly schizophrenia and Parkinson's disease. In contrast, KCa3.1 channels are found in lymphocytes, erythrocytes, fibroblasts, proliferating vascular smooth muscle cells, vascular endothelium and intestinal and airway epithelia and are therefore regarded as targets for various diseases involving these tissues. Since two classes of potent and selective small molecule KCa3.1 blocker, triarylmethanes and cyclohexadienes, have been identified, several of these postulates have already been validated in animal models. The triarylmethane ICA-17043 is currently in phase III clinical trials for sickle cell anemia while another triarylmethane, TRAM-34, has been shown to prevent vascular restenosis in rats and experimental autoimmune encephalomyelitis in mice. Experiments showing that a cyclohexadiene KCa3.1 blocker reduces infarct volume in a rat subdural hematoma model further suggest KCa3.1 as a target for the treatment of traumatic and possibly ischemic brain injury. Taken together KCa2 and KCa3.1 channels constitute attractive new targets for several diseases that currently have no effective therapies.

Original languageEnglish (US)
Pages (from-to)1437-1457
Number of pages21
JournalCurrent Medicinal Chemistry
Volume14
Issue number13
DOIs
StatePublished - Jun 2007

Fingerprint

Intermediate-Conductance Calcium-Activated Potassium Channels
Small-Conductance Calcium-Activated Potassium Channels
Apamin
Modulators
Cyclohexenes
Calcium-Activated Potassium Channels
Subdural Hematoma
Phase III Clinical Trials
Calcium Signaling
Autoimmune Experimental Encephalomyelitis
Rats
Memory Disorders
Vascular Endothelium
Sickle Cell Anemia
Ataxia
Intestinal Mucosa
Structure-Activity Relationship
Vascular Smooth Muscle
Membrane Potentials
Brain Injuries

Keywords

  • Calcium-activated potassium channel
  • KCa2.1
  • KCa2.2
  • KCa2.3
  • KCa3.1
  • Modulators
  • Pharmacology

ASJC Scopus subject areas

  • Organic Chemistry
  • Biochemistry, Genetics and Molecular Biology(all)
  • Biochemistry
  • Pharmacology

Cite this

Modulators of small- and intermediate-conductance calcium-activated potassium channels and their therapeutic indications. / Wulff, Heike; Kolski-Andreaco, Aaron; Sankaranarayanan, Ananthakrishnan; Sabatier, Jean Marc; Shakkottai, Vikram.

In: Current Medicinal Chemistry, Vol. 14, No. 13, 06.2007, p. 1437-1457.

Research output: Contribution to journalArticle

Wulff, Heike ; Kolski-Andreaco, Aaron ; Sankaranarayanan, Ananthakrishnan ; Sabatier, Jean Marc ; Shakkottai, Vikram. / Modulators of small- and intermediate-conductance calcium-activated potassium channels and their therapeutic indications. In: Current Medicinal Chemistry. 2007 ; Vol. 14, No. 13. pp. 1437-1457.
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