Multicellular living organisms and unmodified parts thereof and – Method of using a transgenic nonhuman animal in an in vivo...
Reexamination Certificate
2000-04-27
2004-11-02
Woitach, Joseph T. (Department: 1632)
Multicellular living organisms and unmodified parts thereof and
Method of using a transgenic nonhuman animal in an in vivo...
C800S008000, C800S013000, C435S455000, C435S069100
Reexamination Certificate
active
06812376
ABSTRACT:
BACKGROUND OF THE INVENTION
The invention relates to the diagnosis and treatment of conditions associated with serotonin-mediated cellular responses.
The biogenic amine serotonin plays a role in the modulation of neuronal synaptic events as well as non-neuronal cellular signaling. Serotonin acts by binding to receptors on a variety of cells. These receptors fall into two broad functional and structural categories, those acting through G-proteins to mediate intracellular signaling, and those that form ion channels. It is generally believed that serotonim may act by binding to either G-protein-coupled seven-pass transmembrane receptors, or serotonin-gated cation channels. There are six major classes of G-protein-coupled receptors, each with numerous subtypes. Thus far, there is only one class of serotonin-gated ion channels, the 5-HT
3
receptor. G-protein-coupled responses can be either excitatory or inhibitory upon activation by serotonin. Activation of G-protein-coupled receptors by serotonin generally mediates responses which are slower-acting and longer-lasting, while ion channels mediate fast-acting and transitory responses. The 5-HT
3
receptor, comprised of the conducting subunit, 5-HT
3a
and a regulatory subunit, 5-HT
3b
appears to exclusively elicit excitatory responses that are generally fast-acting and transitory.
The 5-HT
3
receptor is selectively permeable to cations only, such as Na
+
or K
+
, and is very slightly permeable to Ca
2+
. The influx of cations, such as Na
+
into a cell results in depolarization and excitatory neurotransmission. Efflux of cations, such as K
+
hyperpolarizes the cell, thereby reducing the likelihood of excitation, and generally leads to inhibitory neurotransmission. Since the resting membrane of a typical cell
euron is much less permeable to Na
+
influx than to K
+
efflux, the opening of a non-selective Na
+
/K
+
channel, such as the 5-HT
3
receptor leads to a dramatic influx of Na
+
, leading to depolarization and excitation.
Serotonin has been implicated in the etiology of many disease states, including depression, panic disorders, obsessive compulsive disorder, cardiac abnormalities, sleep disorders, eating disorders, nausea and vomiting, gastrointestinal cramps, and migraines. G-protein-coupled serotonin receptors have been implicated in the control of mood (5-HT
1A
), migraine (5-HT
1B
), pain perception (5-HT
1D
), smooth muscle contraction (5-HT
2A
, 5-HT
7
), anxiety (5-HT
2B
), and nausea (5-HT
4
). Activation of the 5-HT
3
receptor by serotonin can either stimulate or inhibit cardiac function, induce vasodilation, affect lung and intestinal function, cause pain and sensitization of nociceptive neurons, and induce nausea and vomiting. Not surprisingly, many treatments for these disorders are thought to act through serotonergic pathways.
Several classes of drugs thought to modulate the serotonergic pathway exist. For example, selective serotonin re-uptake inhibitors (SSRIs) are used to treat depression. These antidepressants, including Prozac, Zoloft, and Paxil, are believed to act by potentiating serotonin levels at the synapse. Drugs, such as Imitrex, used to treat migraine headaches, act as selective serotonin receptor agonists. Other groups of drugs used to affect mood include monoamine oxidase inhibitors, and selective serotonin receptor antagonists.
While these drugs are administered to humans to treat the above-described disease states, the patients often unpredictably experience a number of side-effects including insomnia, anxiety, chest pain, hypertension, nausea, anorexia, sweating, chills, vomiting, diarrhea, constipation, decreased libido, and abnormal ejaculation. It has been hypothesized that the side-effects result from multiple receptor activation or inactivation when a serotonin agonist or antagonist is given as a treatment. Some of these improperly activated or inactivated receptors may lead to fast- or slow- acting excitatory responses, or slow-acting inhibitory responses, when really only one specific type of response is desired.
A better understanding of serotonin-associated cellular communication could greatly facilitate the discovery of drugs and therapeutic methodologies to treat a broad range of conditions with fewer of the serious and variable side-effects prevalent with currently available drugs that interface with the serotonin pathway. Exactly how the currently available drugs that interface with the serotonin pathway work is not well understood. Agonists, antagonists, and especially serotonin re-uptake inhibitors could affect numerous serotonin receptor subtypes, and the final outcome may be a combined readout of all these varied, and sometimes antagonistic, pathways. It has been hypothesized that the various undesirable side-effects of a given drug's action is the result of such unwanted activation of the serotonin pathways that are not specific to the condition being treated. Therefore, compounds with a greater specificity for a specific serotonin receptor, for a limited subset of serotonin receptors, or for a specific subtype of a particular class of serotonin receptors would be invaluable to the field of therapeutics for serotonin-mediated disease states.
SUMMARY OF THE INVENTION
We have discovered a serotonin-gated ion channel, MOD-1, that is exclusively permeable to chloride ions, and is not permeable to sodium, potassium, or calcium ions. Activation of this anion channel is most likely to result in an inhibitory response. In some circumstances that are dependent on the reversal potential for chloride (which is a function of the concentration of chloride inside and outside the cell) activation of anion channels could result in an excitatory response. Therefore, it is conceivable that activation of a serotonin-gated anion channel could also result in excitatory neurotransmission.
With the discovery of MOD-1 and the serotonin-gated anion channel that it forms, comes the realization that serotonin may mediate fast-acting, and transitory, inhibitory responses in addition to excitatory responses. It is possible that the activation/inactivation of a MOD-1-like serotonin-gated anion channel, in humans, is associated with some of the effects and/or side-effects of existing serotonin-based drugs. It is also conceivable that many of the serotonin-related diseases are exclusively due to defects in, or associated with, a serotonin-gated anion channel. None of the currently available drugs have been designed to effectively and specifically target this receptor. Therefore, the discoveries of a serotonin-gated anion channel and the gene that encodes it are invaluable tools for use in discovering diagnostic and therapeutic compounds for the detection and treatment of conditions associated with serotonin-mediated cellular responses.
One way in which a serotonin-gated anion channel can be used as a tool in drug discovery is by screening existing drugs or drug candidates for their effects on serotonin-gated anion channel activity. Such an experiment can be done using MOD-1 or other serotonin-gated anion channels from non-mammals, such as nematodes, or from lower mammals or humans. Understanding how drugs affect, or do not affect, this anion channel will lend better insight into the overall effect of a drug's mechanism of action. Also, a better understanding of how this serotonin-gated anion channel is regulated will contribute to a better understanding of how current therapies work. Furthermore, information gained from this screen will permit the development of drugs with higher specificities for a particular type of serotonin-binding receptor that will mediate only the desired response. Such drugs include those which do not activate a serotonin-gated anion channel, but do activate other serotonin receptors; those that act specifically on a serotonin-gated anion channel, but not on other serotonin receptors; or those that activate a subset of the various serotonin receptors.
Methods of drug discovery are not limited to screening available d
Cannon Stephen C.
Horvitz H. Robert
Ranganathan Rajesh
Bieker-Brady Kristina
Clark & Elbing LLP
Woitach Joseph T.
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