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. 2010 May;3(3):385-96.
doi: 10.1586/ecp.10.11.

Therapeutic potential of KCa3.1 blockers: recent advances and promising trends

Heike Wulff  1 , Neil A Castle
Affiliations

Therapeutic potential of KCa3.1 blockers: recent advances and promising trends

Heike Wulff et al. Expert Rev Clin Pharmacol. 2010 May.

Abstract

The Ca(2+)-activated K(+) channel K(Ca)3.1 regulates membrane potential and calcium signaling in erythrocytes, activated T and B cells, macrophages, microglia, vascular endothelium, epithelia, and proliferating vascular smooth muscle cells and fibroblasts. K(Ca)3.1 has therefore been suggested as a potential therapeutic target for diseases such as sickle cell anemia, asthma, coronary restenosis after angioplasty, atherosclerosis, kidney fibrosis and autoimmunity, where activation and excessive proliferation of one or more of these cell types is involved in the pathology. This article will review the physiology and pharmacology of K(Ca)3.1 and critically examine the available preclinical and clinical data validating K(Ca)3.1 as a therapeutic target.

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Figures

Figure 1
Figure 1
Properties of KCa3.1 channels. A. Simplified phylogenetic tree of genes for human potassium channel subunits, highlighting in red the two gene families that comprise Ca2+-activated potassium channels and further highlighting the KCNN family which contains the gene for KCa3.1 (KCNN4). B. Illustration of KCa3.1 subunit topology showing the six transmembrane domain signature of this class of channels, along with calmodulin attached to a calmodulin binding domain on the C terminus. The location of the histidine phosphorylation site (H358) known to affect channel activation is also shown. C. Illustration of the homo-tetrameric nature of functional KCa3.1 channels, showing the presence of four calmodulin calcium sensors which accounts for the channel’s steep, highly cooperative sensitivity to changes in intracellular calcium concentration.
Figure 2
Figure 2
Cartoon of the physiological role of KCa3.1. The channel is activated by increases in intracellular calcium following calcium release from the ER (endoplasmatic reticulum), and/or calcium influx through inward-rectifier calcium channels like CRAC (calcium release activated calcium channel) or TRP (transcient receptor potential) channels. PLC; phospholipase C; IP3 inositol-triphosphate; CAM; calmodulin.
Figure 3
Figure 3
Structures of KCa3.1 inhibitors and activators.
See this image and copyright information in PMC

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