Nucleic acid encoding human potassium channel K+ nov1...

Details Nucleic acid encoding human potassium channel K+ nov1... Nucleic acid encoding human potassium channel K+ nov1...

1999-06-18

2002-06-04

Mertz, Prema (Department: 1646)

Organic compounds -- part of the class 532-570 series

Organic compounds

Carbohydrates or derivatives

C435S069100, C435S252300, C435S254110, C435S320100, C435S325000, C435S471000, C435S071100, C435S071200, C530S350000

Reexamination Certificate

active

06399761

ABSTRACT:

BACKGROUND
Ion channels are multi-subunit, membrane bound proteins critical for maintenance of cellular homeostasis in nearly all cell types. Channels are involved in a myriad of processes including modulation of action potentials, regulation of cardiac myocyte excitability, heart rate, vascular tone, neuronal signaling, activation and proliferation of T-cells, and insulin secretion from pancreatic islet cells. In humans, ion channels comprise extended gene families with hundreds, or perhaps thousands, of both closely related and highly divergent family members. The majority of known channels regulate the passage of sodium (Na
+
), chloride (Cl
−
), calcium (Ca
++
) and potassium (K
+
) ions across the cellular membrane.
Given their importance in maintaining normal cellular physiology, it is not surprising that ion channels have been shown to play a role in heritable human disease. Indeed, ion channel defects are involved in predisposition to epilepsy, cardiac arrhythmia (long QT syndrome), hypertension (Bartter's syndrome), cystic fibrosis, (defects in the CFTR chloride channel), several skeletal muscle disorders (hyperkalemic periodic paralysis, paramyotonia congenita, episodic ataxia) and congenital neural deafness (Jervell-Lange-Nielson syndrome), amongst others.
The potassium channel gene family is believed to be the largest and most diverse ion channel family. K
+
channels have critical roles in multiple cell types and pathways, and are the focus of significant investigation. Four human conditions, episodic ataxia with myokymia, long QT syndrome, epilepsy and Bartter's syndrome have been shown to be caused by defective K
+
ion channels. As the K
+
channel family is very diverse, and given that these proteins are critical components of virtually all cells, it is likely that abnormal K
+
channels will be involved in the etiology of additional renal, cardiovascular and central nervous system disorders of interest to the medical and pharmaceutical community.
The K
+
channel superfamily can be broadly classified into groups, based upon the number of transmembrane domain (TMD) segments in the mature protein. The mink (IsK) gene contains a single TMD and although not a channel by itself, minK associates with different K
+
channel subunits, such as KvLQT1 and HERG to modify the activity of these channels. The inward rectifying K+ channels (GIRK, IRK, CIR, ROMK) contain 2 TMD domains and a highly conserved pore domain. Twik-1 is a member of the newly emerging 4TMD K
+
channel subset. Twik-like channels (leak channels) are involved in maintaining the steady-state K
+
potentials across membranes and therefore the resting potential of the cell near the equilibrium potential for potassium (Duprat et al. (1997)
EMBO J
16(17):5464-5471). These proteins are particularly intriguing targets for therapeutic regulation. The 6TMD, or Shaker-like channels, presently comprise the largest subset of known K
+
channels. The slopoke (sIo) related channels, or Ca
++
regulated channels apparently have either 10 TMD, or 6 TMD with 4 additional hydrophobic domains.
Four transmembrane domain, tandem pore domain K+ channels (4T/2P channels) represent a new family of potassium selective ion channels involved in the control of background membrane conductances. In mammals, five channels fitting the 4T/2P architecture have been described: TWIK, TREK, TASK-1, TASK-2 and TRAAK. The 4T/2P channels all have distinct characteristics, but are all thought to be involved in maintaining the steady-state K
+
potentials across membranes and therefore the resting potential of the cell near the equilibrium potential for potassium (Duprat et al. (1997)
EMBO J
16(17):5464-5471). These proteins are particularly intriguing targets for therapeutic regulation. Within this group, TWIK-1, TREK-1 and TASK-1 and TASK-2 are widely distributed in many different tissues, while TRAAK is present exclusively in brain, spinal cord and retina. The 4T/2P channels have different physiologic properties; TREK-1 channels, are outwardly rectifying (Fink et al. (1996)
EMBO J
15(24):6854-62), while TWIK-1 channels, are inwardly rectifying (Lesage et al. (1996)
EMBO J
15(5):1004-11. TASK channels are regulated by changes in PH while TRAAK channels are stimulated by arachidonic acid (Reyes et al. (1998)
JBC
273(47):30863-30869).
The degree of sequence homology between different K
+
channel genes is substantial. At the amino acid level, there is about 40% similarity between different human genes, with distinct regions having higher homology, specifically the pore domain. It has been estimated that the K+ channel gene family contains approximately 10
2
-10
3
individual genes. Despite the large number of potential genes, an analysis of public sequence databases and the scientific literature demonstrates that only a small number, approximately 20-30, have been identified. This analysis suggests that many of these important genes remain to be identified.
Potassium channels are involved in multiple different processes and are important regulators of homeostasis in nearly all cell types. Their relevance to basic cellular physiology and role in many human diseases suggests that pharmacological agents could be designed to specific channel subtypes and these compounds then applied to a large market (Bulman, D. E. (1997)
Hum Mol Genet
6:1679-1685; Ackerman, M. J. and Clapham D. E. (1997)
NEJM
336:1575-1586, Curran, M. E. (1998)
Current Opinion in Biotechnology
9:565-572). The variety of therapeutic agents that modulate K+ channel activity reflects the diversity of physiological roles and importance of K+ channels in cellular function. A difficulty encountered in therapeutic use of therapeutic agents that modify K+ channel activity is that the presently available compounds tend to be non-specific and elicit both positive and negative responses, thereby reducing clinical efficacy. To facilitate development of specific compounds it is desirable to have further characterize novel K+ channels for use in in vitro and in vivo assays.
Relevant Literature
A large body of literature exists in the general area of potassium channels. A review of the literature may be found in the series of books, “The Ion Channel Factsbook”, volumes 1-4, by Edward C. Conley and William J. Brammar, Academic Press. An overview is provided of: extracellular ligand-gated ion channels (ISBN: 0121844501), intracellular ligand-gated channels (ISBN: 012184451X), Inward rectifier and intercellular channels (ISBN: 0121844528), and voltage gated channels (ISBN: 0121844536). Hille, B. (1992) “Ionic Channels of Excitable Membranes”, 2
nd
Ed. Sunderland MA:Sinauer Associates, also reviews potassium channels.
Jan and Jan (1997)
Annu. Rev. Neurosci.
20:91-123 review cloned potassium channels from eukaryotes and prokaryotes. Ackerman and Clapham (1997)
N. Engl. J. Med.
336:1575-1586 discuss the basic science of ion channels in connection with clinical disease. Bulman (1997)
Hum. Mol. Genet.
6:1679-1685 describe some phenotypic variation in ion channel disorders.
Stephan et al. (1994)
Neurology
44:1915-1920 describe a pedigree segregating a myotonia with muscular hypertrophy and hyperirritability as an autosomal dominant trait (rippling muscle disease, Ricker et al. (1989)
Arch. Neurol.
46405-408). Electromyography demonstrated that mechanical stimulation provoked electrically silent contractions. The responsible gene was localized to the distal end of the long arm of chromosome 1, in a 12-cM region near D1S235.
Type II pseudohypoaldosteronism is the designation used for a syndrome of chronic mineralocorticoid-resistant hyperkalemia with hypertension. The primary abnormality in type II PHA is thought to be a specific defect of the renal secretory mechanism for potassium, which limits the kaliuretic response to, but not the sodium and chloride reabsorptive effect of, mineralocorticoid. By analysis of linkage in families with autoso

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