Neurons expressing the vasoactive intestinal peptide receptor 2 (VPAC2), also known as VIP receptor 2 or Vasoactive Intestinal Peptide Receptor 2, are widely distributed throughout the central nervous system. VPAC2 is a G protein-coupled receptor that binds both vasoactive intestinal peptide (VIP) and pituitary adenylate cyclase-activating polypeptide (PACAP). These neurons play important roles in neuroprotection, circadian rhythm regulation, and immune modulation.
VPAC2-expressing neurons are found in:
- Suprachiasmatic nucleus (SCN) — key location for circadian rhythm regulation
- Cerebral cortex — throughout cortical layers
- Hippocampus — in all hippocampal regions
- ** — particularly in central nucleus
- HAmygdalaypothalamus** — in multiple hypothalamic nuclei
- Brainstem — in regions controlling autonomic functions
VPAC2 neurons in the SCN:
- Mediate VIP signaling in circadian clock
- Synchronize circadian rhythms
- Regulate light-entrained responses
- Control sleep-wake cycles
VPAC2 activation provides neuroprotective effects through:
- Anti-apoptotic signaling (via PACAP)
- Anti-inflammatory responses
- Reduction of excitotoxicity
- Promotion of neural progenitor proliferation
¶ Learning and Memory
- Modulates hippocampal synaptic plasticity
- Influences memory consolidation
- Involved in fear conditioning
- VPAC2 on neurons interacts with immune cells
- Modulates neuroinflammation
- Affects blood-brain barrier function
- VPAC2/PACAP signaling is neuroprotective in AD
- PACAP deficiency observed in AD brains
- VPAC2 agonists being explored as therapy
- May reduce amyloid toxicity
- VPAC2 provides dopaminergic neuroprotection
- PACAP-VPAC2 axis supports neuron survival
- Potential for disease modification
- VPAC2 modulates neuroinflammation
- PACAP therapy shows promise in MS models
¶ Stroke and Ischemia
- VPAC2 activation reduces ischemic damage
- Promotes neuronal survival after stroke
VPAC2 couples to Gs proteins:
- Activates adenylyl cyclase → increases cAMP
- Stimulates PKA signaling
- Activates MAP kinase pathways
- Modulates calcium channels
VPAC2 is a therapeutic target for:
- Circadian rhythm disorders
- Neurodegenerative diseases
- Stroke treatment
- Inflammatory conditions
- VPAC2 receptor in circadian rhythm (2018)
- PACAP/VPAC2 neuroprotection in Alzheimer's disease (2020)
- VPAC2 and PACAP in Parkinson's disease (2019)
- VIP signaling in neuroinflammation (2021)
- VPAC2 in synaptic plasticity and memory (2017)