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Brain Damage-linked ATP Promotes P2X7 Receptors Mediated Pineal N-acetylserotonin Release

Kassiano S Sousa1, Caroline L Quiles1, Sandra M Muxel1

  • 1Laboratory of Chronopharmacology, Department of Physiology, Institute of Bioscience, University of São Paulo, São Paulo 05508-090, Brazil.

Neuroscience
|July 7, 2022
PubMed

Insights

The pineal gland uses ATP to regulate melatonin (MEL) production. Low ATP boosts MEL, while high ATP converts N-acetylserotonin (NAS) to MEL, aiding brain injury responses.

Area of Science:

  • Neuroendocrinology
  • Cellular signaling
  • Immunology

Background:

  • The pineal gland produces melatonin (MEL), which regulates leukocyte activity.
  • Melatonin synthesis is inhibited by inflammatory signals, promoting leukocyte migration.
  • Adenosine triphosphate (ATP) modulates noradrenaline (NAd)-induced MEL synthesis via P2Y1 receptors and inhibits N-acetylserotonin (NAS) to MEL conversion via P2X7 receptors.

Purpose of the Study:

  • To investigate the effects of focal ATP increases on pineal gland activity and melatonin synthesis in vivo.
  • To elucidate the role of ATP signaling through P2Y1 and P2X7 receptors in regulating melatonin production and its precursors.
  • To understand the pineal gland's response to cellular damage signals within the brain.

Main Methods:

  • Adult rats received intraventricular injections of varying ATP doses (0.3, 1.0, 3.0 µg) and a P2X7 receptor agonist (BzATP).
  • Pineal gland and blood samples were analyzed for melatonin (MEL) and N-acetylserotonin (NAS) content.
  • Gene expression of melatonergic enzymes in different brain structures (cortex, cerebellum) was assessed.

Main Results:

  • Low ATP doses (0.3, 1.0 µg) increased nocturnal pineal MEL output.
  • High ATP dose (3.0 µg) and BzATP administration elevated NAS levels in both the pineal gland and blood.
  • Cortical MEL levels increased, while cerebellar MEL remained unchanged, indicating structure-dependent responses.
  • Changes in gene expression of synthetic and metabolizing melatonergic enzymes correlated with observed MEL and NAS levels.

Conclusions:

  • The pineal gland responds to focal increases in brain ATP, modulating melatonin synthesis.
  • ATP signaling via P2X7 receptors plays a critical role in converting NAS to MEL, particularly under conditions of cellular damage.
  • The pineal gland acts as a first-line sensor for brain cell death, utilizing the NAS-to-MEL pathway.
Keywords:
BzATPMELN-acetylserotoninPurinergic signalingacetylserotonin N-methyltransferase (ASMT)serotonin-N-acetyltransferase (SNAT)

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