Associate editor: M.A. RogawskiK+ channels as therapeutic drug targets
Introduction
K+ channels have been recognized as potential targets for therapeutic drugs for many years. Unfortunately, progress toward identifying selective K+ channel modulators has been severely hampered by the need to use native currents and primary cells in the drug-screening process. In fact, until quite recently, only ATP-sensitive K+ channels and cardiac-delayed rectifier K+ channels (see 2 K, 6.2 K) have been amenable to the drug discovery process. ATP-sensitive K+ channels, in particularly, have been the focus of intense effort in the pharmaceutical industry over the past two decades, and a large number of ATP-sensitive K+-channel openers and blockers have been described. The fact that ATP-sensitive K+-channel openers were generally referred to as “potassium channel openers” or “KCOs” was perhaps indicative of the complete absence of openers of other classes of K+ channels during most of the 1980s and 1990s. Over the last decade, however, the human genome project, together with an intense cloning effort, has identified more than 80 K+ channel-related genes. This, coupled with progress toward understanding the distribution and contribution of K+ channel genes to native currents, and advances in drug-screening technologies, has made K+ channels increasingly attractive as therapeutic drug targets. K+ channel modulators are no longer restricted to openers and blockers of ATP-sensitive K+ channels. Openers and blockers of many K+ channels have now been described, and currently, several highly potent and selective agents are being evaluated in clinical trials for the treatment of a variety of human diseases.
Section snippets
K+ channel physiology
K+ channels are a ubiquitous family of membrane proteins that play critical roles in a wide variety of physiological processes, including the regulation of heart rate, muscle contraction, neurotransmitter release, neuronal excitability, insulin secretion, epithelial electrolyte transport, cell volume regulation, and cell proliferation. A highly diverse set of K+ channels has evolved in order to serve such a wide variety of roles. Some K+ channels, i.e., voltage-gated K+ (Kv) channels, are
K+ channel classification
Over the past decade, there has been an intense effort to clone and characterize mammalian K+ channels. To date, more than 80 K+ channel-related genes (i.e., pore-forming subunits or modulatory subunits) have been cloned and characterized. A brief summary of K+ channel classification is presented in the following sections.
K+ channel assembly
Of the K+-selective channels, the most structural information is known about Kv channels. Kv channels contain four α-subunits that surround a water-filled, K+-selective pore (MacKinnon, 1991). Kv channels can be formed from four identical α-subunits (homomultimers) or from combinations of two or more different α-subunits (heteromultimers). Only α-subunits from the same subfamily are capable of co-assembling to form heteromultimers, i.e., Kv1.x is capable of forming heterotetrameric channels
Relationship between cloned subunits and native K+ currents
As described in the preceding sections, recent cloning efforts have identified a large and diverse set of K+ channel-related genes. Further diversity is generated by alternative splicing of gene products Schwarz et al., 1988, Luneau et al., 1991, Butler et al., 1993, Yano et al., 1994, England et al., 1995, heteromultimeric assembly of α-subunits and assembly with modulatory β-subunits. Despite the seemingly endless possibilities for channel diversity, a combination of biophysical,
K+ channels, immunosuppression, and cell proliferation
Sustained Ca2+ influx through store-operated, Ca2+-release activated Ca2+ channels (ICRAC) is an important step in the cellular signaling pathway that leads to proliferation in a variety of cell types, including T-lymphocytes, prostate cancer cells, and fibroblasts. K+ channels play an essential role in this process by maintaining a favorable electrical driving force for Ca2+ entry. Accordingly, blockers of these K+ channels may inhibit cell proliferation and may be of potential benefit in
Future directions for therapeutic exploitation of K+ channels
As a result of an impressive effort over the last 15 years, more than 80 K+ channels and K+ channel-related genes have been identified. Heteromeric channel assembly, inclusion of modulatory β-subunits, and alternative splicing of gene products can generate seemingly endless possibilities for channel diversity. Despite this, a combination of biophysical, pharmacological, and genetic approaches has started to provide an understanding of the molecular composition of many important native K+
Acknowledgements
The author would like to thank Dr. Neil Castle, Dr. Douglas Krafte, and Dr. Kay Wagoner for helpful comments during the preparation of the review.
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