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Ion Channels and Transporters of Epithelia in Health and Disease pp 857–899Cite as

Recent Developments in the Pharmacology of Epithelial Ca2+-Activated K+ Channels

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Part of the book series: Physiology in Health and Disease ((PIHD))

Abstract

Calcium (Ca2+)-activated potassium (K+) channels (KCa) in epithelia serve important functions in fluid and salt secretion and may be attractive targets for drug development for epithelial disorders, such as cystic fibrosis, diarrhoea, COPD, polycystic kidney disease, and glaucoma. Two very different types of KCa channels are generally found in epithelia: the big conductance, Ca2+-activated K+ channel (BK, KCa1.1), and the intermediate conductance, Ca2+-activated K+ channel (IK, KCa3.1). These channels are differentially expressed in various cells and tissues and serve different physiological and potentially also pathophysiological functions in epithelia.

The present chapter aims at giving a brief review of the physiology and function of BK and IK channels, a description of the classical pharmacology of these channels, and an in-depth overview of the status of drug discovery and development programmes in the pharmaceutical industry as well as academia, based on both literature and patent references, and it ends with a discussion of recent advances in the understanding of the molecular pharmacology of these channels. The review is comprehensive and the focus is throughout ion channel pharmacology with exemplary cases from the epithelial as well as non-epithelial fields.

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Abbreviations

BK channel:

Big conductance Ca2+-activated K+ channel, KCa1.1

Cam:

Calmodulin

ChTx:

Charybdotoxin

COPD:

Chronic obstructive pulmonary disorder

CFTR:

Cystic fibrosis transmembrane conductance regulator

CYP:

Cytochrome P450

FLIPR:

Fluorescent imaging plate reader

IbTx:

Iberiotoxin

IK channel:

Intermediate conductance Ca2+-activated K+ channel KCa3.1

IV relation:

Current through the ion channel depicted as function of the membrane potential

KCa :

Ca2+-activated K+ channel including all SK IK, and BK channels (IUPHAR nomenclature)

k off :

Kinetic off-rate of ligand (inhibitor or activator) binding to the channel (s−1)

k on :

Kinetic on-rate of ligand binding to the channel (M−1 × s−1)

Kv :

Voltage-gated K channel (IUPHAR nomenclature)

KCNN :

Potassium intermediate/small conductance calcium-activated channel subfamily N (gene name)

KCNMA :

Potassium large conductance calcium-activated channel subfamily M, alpha member 1 (gene name)

KCNMB :

Potassium large conductance calcium-activated channel subfamily M, beta member 1 (gene name)

P2Y:

Purinergic 2Y receptors

pS:

Conductance though a single ion channel measured by the unit 10−12 Siemens

RKC domain:

Regulator of K+ conductance domain

SK channel:

Small conductance Ca2+-activated K+ channel (KCa2.1, KCa2.2, KCa2.3)

TEA:

Tetraethylammonium

TM:

Transmembrane domain

TMEM16A:

Transmembrane protein member 16A, Ca2+-activated Cl− channel

V m :

Membrane potential (mV)

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Authors and Affiliations

  1. Grünenthal GmbH, Zieglerstraße 6, 52078, Aachen, Germany

    Antonio Nardi

  2. Panum Institute, University of Copenhagen, Blegdamsvej 3, 2200, Copenhagen N, Denmark

    Søren-Peter Olesen

  3. Saniona A/S, Baltorpvej 154, 2750, Ballerup, Denmark

    Palle Christophersen

Authors
  1. Antonio Nardi
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  2. Søren-Peter Olesen
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  3. Palle Christophersen
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Correspondence to Antonio Nardi .

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Editors and Affiliations

  1. Department of Physiology, University of Otago , Dunedin, Otago, New Zealand

    Kirk L. Hamilton

  2. Department of Cell Biology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA

    Daniel C Devor

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Nardi, A., Olesen, SP., Christophersen, P. (2016). Recent Developments in the Pharmacology of Epithelial Ca2+-Activated K+ Channels. In: Hamilton, K., Devor, D. (eds) Ion Channels and Transporters of Epithelia in Health and Disease. Physiology in Health and Disease. Springer, New York, NY. https://doi.org/10.1007/978-1-4939-3366-2_26

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