Pharmacology of Small- and Intermediate-Conductance Calcium-Activated Potassium Channels
| Autor: | Brandon M. Brown, Heike Wulff, Palle Christophersen, Heesung Shim |
|---|---|
| Rok vydání: | 2020 |
| Předmět: |
Calmodulin
Small-Conductance Calcium-Activated Potassium Channels Potassium Druggability chemistry.chemical_element Toxicology Cardiovascular Medical and Health Sciences Article Calcium in biology K(Ca)2.2 K(Ca)3.1 calcium-activated potassium channel K(Ca)2.3 medicine Potassium Channel Blockers Animals Humans Pharmacology & Pharmacy Binding site Pharmacology Binding Sites biology Membrane hyperpolarization Biological Sciences Intermediate-Conductance Calcium-Activated Potassium Channels Calcium-activated potassium channel gating modulation Mechanism of action chemistry Cardiovascular Diseases 5.1 Pharmaceuticals biology.protein Biophysics KCa2.3 KCa2.2 KCa3.1 Generic health relevance medicine.symptom Nervous System Diseases |
| Zdroj: | Annual review of pharmacology and toxicology, vol 60, iss 1 Annu Rev Pharmacol Toxicol |
| Popis: | The three small-conductance calcium-activated potassium (KCa2) channels and the related intermediate-conductance KCa3.1 channel are voltage-independent K+ channels that mediate calcium-induced membrane hyperpolarization. When intracellular calcium increases in the channel vicinity, it calcifies the flexible N lobe of the channel-bound calmodulin, which then swings over to the S4-S5 linker and opens the channel. KCa2 and KCa3.1 channels are highly druggable and offer multiple binding sites for venom peptides and small-molecule blockers as well as for positive- and negative-gating modulators. In this review, we briefly summarize the physiological role of KCa channels and then discuss the pharmacophores and the mechanism of action of the most commonly used peptidic and small-molecule KCa2 and KCa3.1 modulators. Finally, we describe the progress that has been made in advancing KCa3.1 blockers and KCa2.2 negative- and positive-gating modulators toward the clinic for neurological and cardiovascular diseases and discuss the remaining challenges. |
| Databáze: | OpenAIRE |
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