Pharmacological differences between human and mouse P2X4 receptor explored using old and new tools.

Area of Science:

• Pharmacology
• Neuroscience
• Cardiovascular Research

Background:

• The P2X4 receptor is a key target for cardiovascular, inflammatory, and neurological conditions.
• Selective P2X4 antagonists are available, but agonist selectivity requires further study.
• Species-specific pharmacological differences necessitate careful tool selection for P2X4 research.

Purpose of the Study:

• To systematically compare the agonist and antagonist pharmacology of human and mouse P2X4 receptors.
• To identify key differences in P2X4 receptor activation and inhibition between species.
• To guide the selection of appropriate pharmacological tools for P2X4 research in human and mouse models.

Main Methods:

• Utilized 1321N1 cells expressing either human or mouse P2X4 orthologues.
• Performed systematic comparisons of various known P2X4 agonists and antagonists.
• Analyzed and ranked the potency of different compounds for human and mouse P2X4.

Main Results:

• Established distinct rank orders of agonist potency for human (ATP > 2-MeSATP > αβmeATP = BzATP > CTP = γ-[(propargyl)-imido]-ATP) and mouse (ATP > 2-MeSATP = CTP > ATPγS = γ-[(propargyl)-imido]-ATP = BzATP) P2X4.
• Identified species-specific antagonist potencies, with 5-BDBD and BX-430 showing activity against human but not mouse P2X4.
• Human P2X4 responded to αβmeATP but not ATPγS, while mouse P2X4 showed different sensitivities to CTP, ATPγS, BzATP, and γ-[(propargyl)-imido]-ATP.

Conclusions:

• Significant pharmacological differences exist between human and mouse P2X4 receptors.
• Caution is advised when selecting P2X4 research tools for comparative human-mouse studies.
• Results highlight the importance of species-specific considerations for interpreting P2X4-mediated cellular responses and therapeutic strategies.