Modulatory binding site in potassium channels for screening...

Details Modulatory binding site in potassium channels for screening... Modulatory binding site in potassium channels for screening...

1999-08-03

2002-10-29

Guzo, David (Department: 1636)

Chemistry: molecular biology and microbiology

Measuring or testing process involving enzymes or...

Involving viable micro-organism

C435S004000, C435S006120, C435S007200, C435S007800, C435S375000, C530S350000

Reexamination Certificate

active

06472165

ABSTRACT:

FIELD OF INVENTION
The invention relates to a new, selective modulatory binding site in potassium channels for screening and finding new active ingredients for the treatment of diseases, which can be attributed to a hyper excitation or a deficient excitability of neuronal cells.
BACKGROUND
Potassium channels have various definite functions in excitable cells, and not excitable cells. These functions include, for instance, the control of the membrane potential, the regulation of insulin secretion from pancreatic &bgr;-cells, the control or the release of cytokines from T lymphocytes, the regulation of the salt and water equilibrium in kidney cells, and the control of the electrical excitability and synaptic plasticity of neurons. It is therefore not surprising that the activity of the potassium channels is subject to a plurality of control mechanisms, which include the redox potential of a cell, the secondary messenger systems, namely calcium and cyclo-adenosine monophosphate (c-AMP), protein kinases and phosphatases, and the membrane potential. Moreover, the structures of previously characterized potassium channel proteins have numerous variations of different basic motifs and are thus very heterogeneous. On the basis of these various functions, it is also not surprising that different potassium channels occur ubiquitously in the plant and animal kingdoms (Sewing, S., Röper, J., and Pongs, O.: Structure and function of voltage-gated K
+
channels. Euroforum 2, 21-28, 1996).
Potassium channels selectively fulfill their heterogeneous tasks due to these manifold structures and in conjunction with the very large band width of the modulation paths. Substances, which selectively modulate the potassium channels are interesting medicinal drugs for a plurality of different diseases. Potassium channels are discussed in the literature as targets for the treatment of strokes, epilepsy, Alzheimer's disease, psychiatric diseases, sleep disorders, cardiac arrhythmiasis, diabetes type II, osmotic dysfunctions such as in the case of glaucoma, tumor cell growth, but also for inflammation processes and for learning disorders, for high blood pressure, incontinence and asthma.
It was previously possible to successfully implement the treatment of diabetes, of cardiac arrhythmiasis and of high blood pressure with selective medicinal drugs (Sewing et al., see above).
In 1998, Schröder et al. reported for the first time that a mutation-induced, slight interference with only one member of the large family of potassium channels can substantially interfere with the fragile equilibrium between excitation and inhibition of excitable cells. In the case of this particular channel, it is a heterooligomer consisting of the subunits with the names of KCNQ2 and KCNQ3. The function of this channel is reduced by about 25% through mutation of one of the two subunits. This causes affected patients to suffer epileptic attacks already in early infancy (Schröder, B. C., Kubisch, C., Stein, V., Jentsch, T. J., Moderate loss of function of cyclic-AMP modulated KCNQ2/KCNQ3 K
+
channels causes epilepsy. Nature 396, 687-690, 1998). This channel is the first potassium channel, to which a human disease can be unambiguously assigned. Schröder postulates that a positive modulation of this channel should produce a strong anticonvulsive effect. He concludes that, by increasing the level of the intracellular seconal messenger cAMP, the activity of the channel can be positively affected; in his in vitro systems, he was able to show that the activity of the channel actually increases as the cAMP level increases.
At about the same time, Wang et al. (Wang, H. S., Pan, Z., Shi, W., Brown, B. S., Wymore, R. S., Cohen, U. S., Dixon, J. E., McKinnon, D., KCNQ2 and KCNQ3 potassium channel subunits: molecular correlates of the M-channel. Science 282, 1890-1893, 1998) showed that the above-mentioned heterooligomeric channel, confirmed in man and consist of KCNQ2 and KCNQ3, is the molecular correlate of the M channel, the functions of which were described long ago.
The M channel is formed selectively only in neuronal cells (see Schröder et al., and Wang et al., above) and is coupled there over intracellular signal proteins (G proteins) selectively in the central nervous system to muscarinergic sub-types of the acetylcholine receptor. The channel is not expressed in the peripheral tissue. The activity of the channel is lowered by muscarine agonists and raised by muscarine antagonists.
The muscarine agonist, pilocarpin, initiates severe convulsions in animals. The resulting destruction of the cells, in which the muscarine receptor (and also of the M channel) is expressed, causes the animal to develop spontaneous epileptic episodes after this treatment.
By means of a different muscarine agonist, oxotremorin, an essential tremor, which simulates the tremor of Parkinson's patients, can be initiated in the animal by sub-lethal doses. Muscarine-antagonistic substances are used clinically for the treatment of this tremor.
From these presentations, which are given by way of example, it becomes clear that an indirect modulation of the M channel (initiated over muscarine receptors or caused by an increase in the cAMP level) represents a highly interesting possibility for intervening in different diseases.
In particular, this is to be shown in greater detail for several diseases.
Epilepsy
Epilepsy is characterized by the repeated occurrence of convulsions. It occurs at the rate of 0.5 to 1% of the population. Epileptic convulsions result from an abnormal synchronization and a massive discharge of a large number of nerve cells in a nerve cell association in the brain. Depending on the participation of different regions of the brain, this results in a paroxysmal temporary disturbance in motor activity (motor convulsions), emotional state, behavior or perception (Janz, D. (1985) Epilepsy: Seizures and syndromes. In: Frey, H. H. and Janz, D. eds., Antiepileptic drugs. Handbook of experimental pharmacology, Vol. 74, pp. 3-34, Springer-Verlag, Berlin, Heidelberg, New York, Tokyo); (Porter, R. J., Classification of epileptic seizures and epileptic syndromes. In: Laidlaw J., Richens A., Chadwick D., (eds.): A Textbook of Epilepsy. Churchill Livingstone, N.Y., 1993, pp. 1-22).
However, the convulsion is only one symptom, which principally can be initiated in each individual, when the stimulus for activation and synchronization is sufficiently strong. Epilepsy is therefore characterized by an increased sensitivity to external or internal stimuli for synchronization and activation. The excitability and the sensitivity of the nerve cells is greater in epileptic patients.
As mentioned above, it was possible recently to show that potassium channels, which are composed of the subunits KCNQ2 and KCNQ3, have a decisive controlling effect on the excitability of nerve cells (Schröder et al., supra). A reduction in function of these channels by about 25% already leads to epileptic attacks in infants, who do not have adequate compensatory mechanisms at their disposal. Such a weak reduction in the function of this potassium channel was detected for a genetically determined form of epilepsy, the BFNC (benign familial neonatal convulsions) variety (Schröder et al., supra). This potassium channel can be detected only in the brain and in nerve cells, but not in other tissue (see Schröder et al., supra; and Wang et al., supra).
It has not yet been possible to clarify the genetic cause for other forms of epilepsy. However, the disease is always associated with an increased excitability of nerve cell networks. The current therapy tended to reduce the symptoms of the diseases. Established antiepileptic drugs, such as carbamazepine, phenytoin and lamotrigine act as use-dependent blockers of sodium channels. These channels are necessary in order to conduct cellular excitations along nerve fibers.
Sodium channel blockers reduce the conductance of excitations and in this way have an anticonvulsive action. The underlying hyper-excitation is however not reduced. Other

Affiliated with

Also associated with

Rating

Modulatory binding site in potassium channels for screening... does not yet have a rating. At this time, there are no reviews or comments for this patent.

If you have personal experience with Modulatory binding site in potassium channels for screening..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Modulatory binding site in potassium channels for screening... will most certainly appreciate the feedback.

Rate now

Comments { 0 }

Profile ID: LFUS-PAI-O-2977458