Targetable purinergic receptors P2Y12 and A2b antagonistically regulate bladder function.

Area of Science:

• Urology
• Pharmacology
• Cell Biology

Background:

• Lower urinary tract symptoms (LUTS) are often associated with purine metabolism and purinergic receptor abnormalities.
• The precise mechanisms linking altered purinergic receptor function to LUTS remain largely unknown.

Purpose of the Study:

• To investigate the reciprocal interplay of adenosine diphosphate (ADP) and adenosine signaling via P2Y12 and A2b receptors in regulating bladder function.
• To elucidate the role of these receptors in bladder smooth muscle (BSM) contractility, cell growth, and LUTS phenotypes.

Main Methods:

• Utilized knockout (KO) mouse models lacking P2Y12 or A2b receptors to study bladder phenotypes.
• Assessed BSM contractility, cell growth, and voiding parameters in KO mice.
• Administered drugs targeting P2Y12 and A2b receptors to evaluate therapeutic potential.

Main Results:

• ADP-stimulated P2Y12 receptors induced BSM contraction, while adenosine signaling via A2b receptors inhibited it.
• P2Y12-KO mice exhibited an underactive bladder (UAB) phenotype, whereas A2b-KO mice displayed an overactive bladder (OAB) phenotype.
• Dysregulated BSM contractility and cell growth contributed to the opposing LUTS phenotypes in KO mice.

Conclusions:

• P2Y12 and A2b receptors play critical, opposing roles in regulating bladder function and smooth muscle dynamics.
• Targeting P2Y12 and A2b receptors with pharmacological agents can effectively rescue abnormal bladder phenotypes.
• These receptors represent promising therapeutic targets for managing LUTS in patients.