Type I Taste Receptor Ligands Control VGSC Activity
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Solution Overview
Problem
Current treatments for neurological disorders such as Alzheimer's disease and neuropathic pain associated with chemotherapy lack effective mechanisms to inhibit voltage-gated sodium channels (VGSC) without causing indiscriminate blockade, which can be life-threatening.
Innovation Solution
The method involves using Type I taste receptors, specifically T1R2/T1R3 and T1R1/T1R3, to control VGSC activity indirectly through ligands that bind to these receptors. Amyloid β peptides, sweet amino acids, and umami compounds activate these receptors, regulating VGSC activity. Inhibitors targeting these receptors, such as T1R3 antagonists, are used to suppress enhanced VGSC activity associated with neurological disorders.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If voltage-gated sodium channels (VGSC) are blocked to inhibit neuronal hyperactivity, then neuronal hyperactivity is suppressed, but life-threatening side effects occur due to indiscriminate blockade
Solution Approach 1:
The patent introduces Type I taste receptors (T1Rs) as intermediary molecules that mediate the interaction between amyloid β peptides and VGSC. By targeting T1Rs with specific ligands (agonists or antagonists), the patent achieves selective control of VGSC activity without direct indiscriminate blocking, thus resolving the contradiction between effective inhibition and harmful side effects
Solution Approach 2:
The patent applies local quality by targeting specific receptor subtypes (T1R2/T1R3 and T1R1/T1R3) expressed in particular neuronal populations. This selective targeting allows inhibition of VGSC activity in specific brain regions involved in neuronal hyperactivity while avoiding widespread indiscriminate blockade that causes life-threatening effects
2Reliability
If amyloid β peptides bind to Type I taste receptors to enhance VGSC activity, then neuronal hyperactivity occurs, but the mechanism for selective inhibition is unclear
Solution Approach 1:
The patent identifies Type I taste receptors as intermediary molecules that transmit the effect of amyloid β peptides to VGSC. By utilizing this intermediary pathway, the patent simplifies the inhibition mechanism to targeting T1Rs with specific ligands, rather than directly addressing the complex amyloid β-VGSC interaction
Solution Approach 2:
The patent uses synthetic ligands that copy or mimic the binding characteristics of amyloid β peptides to T1Rs. These ligands (such as sweet amino acids or umami compounds) can be designed to selectively activate or block T1R signaling, providing a simplified and controllable mechanism for VGSC regulation
3Object-affected harmful factors
If selective receptor targeting is used to inhibit VGSC, then side effects are minimized, but the complexity of identifying and targeting specific receptors increases
Solution Approach 1:
The patent identifies Type I taste receptors as multi-functional molecules that serve both taste perception and VGSC regulation functions. This universality simplifies the targeting approach, as a single receptor family (T1Rs) with specific subunits (T1R2/T1R3, T1R1/T1R3) can be used to control VGSC activity in multiple neuronal contexts, reducing the need to develop and manage multiple separate targeting systems
Applied Scientific Principles
This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.
Function Achieved in This Case
This approach effectively inhibits excessive VGSC activity, reducing neuronal hyperactivity and associated pain, while minimizing the risk of life-threatening side effects by selectively targeting the receptors involved in VGSC regulation.
Implementation Method 1
Type I taste receptors, specifically T1R2/T1R3 and T1R1/T1R3, are used to control VGSC activity indirectly through ligands that bind to these receptors
Implementation Method 2
Amyloid β peptides, sweet amino acids, and umami compounds activate these receptors, regulating VGSC activity
Implementation Method 3
Inhibitors targeting these receptors, such as T1R3 antagonists, are used to suppress enhanced VGSC activity associated with neurological disorders
Data Source
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AI summary
The present invention pertains to a method for controlling a membrane potential-dependent ion channel (VGSC or the like) through a type I taste receptor present in a nerve cell or the like. In the present invention, it has been found that an A β peptide, or a sweet amino acid or an umami substance specifically binds to a type I taste receptor on the surface of a nerve cell to exert an agonist-like or antagonist-like action, thereby amplifying or suppressing a VGSC active current. Moreover, with the binding of an Aβ peptide or the like to a type I taste receptor, the amplification of a VGSC active current occurs, the overactivity of nerve cells causing epileptiform attack occurs, and a large number of substances, which can effectively suppress the amplification of the VGSC active current, among ligand substances that specifically bind to the type I taste receptor, can be found. The present invention provides: a type I taste receptor-specific ligand substance that can control the amplification or suppression of a VGSC active current; and a pharmaceutical composition for preventing or treating various neurodegenerative diseases, such as Alzheimer's disease (AD), due to the amplification of a VGSC active current caused by the binding of an Aβ peptide or the like to a type I taste receptor. Moreover, a method for using, as a target receptor, a type I taste receptor present in a nerve cell or the like to screen a ligand substance for controlling a VGSC or the like in the cell is also provided. Furthermore, the present invention provides a method in which a solution that reproduces the type and concentration of an Aβ peptide contained in the cerebrospinal fluid and serum of a patient with Alzheimer-type dementia is used, and the Aβ peptide contained in the CFS and serum of the patient assesses pathology. Specifically, provided is: a method for assessing the form and dynamic state of cells and the activity of a neurite by using an optical microscope; or a method for assessing the impedance change in a vascular epithelial cell.