Connexins and pannexins are transmembrane channel proteins that form gap junctions and hemichannels, allowing direct communication between cells and between the intracellular and extracellular compartments. In the central nervous system, these channels play critical roles in neuronal function, glial signaling, and neuroimmune interactions. Dysregulation of connexin and pannexin signaling has been implicated in the pathogenesis of neurodegenerative diseases including Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and stroke. This pathway page explores the molecular mechanisms by which these channels contribute to neurodegeneration and their potential as therapeutic targets.
Connexins are a family of 21 members in humans, named by their molecular weight (e.g., Cx26 = 26 kDa). Key connexins in the CNS include: [1]
| Connexin | Gene | Primary CNS Expression | Functions | [2]
|----------|------|----------------------|-----------| [3]
| Cx36 | GJC2 | Neurons (retinal amacrine, interneurons) | Electrical synapses | [4]
| Cx43 | GJA1 | Astrocytes, ependymal cells | Metabolic coupling, calcium waves | [5]
| Cx30 | GJB6 | Astrocytes | Potassium buffering, BBB function | [6]
| Cx26 | GJB2 | Oligodendrocytes, astrocytes | Myelin maintenance | [7]
| Cx32 | GJB1 | Oligodendrocytes, Schwann cells | Myelin sheath function | [8]
| Cx45 | GJA7 | Neurons, astrocytes | Synaptic transmission | [9]
Pannexins (PANX1, PANX2, PANX3) are a distinct family of channel proteins that primarily form single-membrane hemichannels rather than gap junction channels:
Gap junctions direct cell-to-cell communication by connecting the cytoplasm of adjacent cells:
Unpaired hemichannels allow communication between intracellular and extracellular compartments:
| Compound | Target | Development Stage | Evidence |
|---|---|---|---|
| Carbenoxolone | Cx hemichannels | Preclinical | Blocks ATP release, neuroprotective in stroke models |
| Octanol | Cx36 gap junctions | Preclinical | Reduces seizure activity |
| Gap26 | Cx43 mimetic peptide | Preclinical | Reduces infarct size, improves functional outcome |
| BBG (Brilliant Blue G) | P2X7 receptor | Preclinical | Blocks PANX1 downstream effects |
| Probenecid | PANX1 | Approved (gout) | Blocks PANX1 currents |
Orellana et al. ATP release through pannexon hemichannels in brain ischemia (2020). 2020. ↩︎
Froger et al. Connexin pathology in Alzheimer's disease (2022). 2022. ↩︎
Kimelberg et al. Astrocytic connexin43 channels in Parkinson's disease (2021). 2021. ↩︎
Kelley et al. Pannexin 1 and P2X7 in amyotrophic lateral sclerosis (2023). 2023. ↩︎
Fasciani et al. Hemichannel blockers in stroke therapy (2020). 2020. ↩︎
Abudara et al. Connexin43 hemichannels and neuroinflammation (2019). 2019. ↩︎
Bennett et al. Gap junction communication in neurodegenerative diseases (2020). 2020. ↩︎
Sanchez-Arias et al. Therapeutic targeting of connexin hemichannels (2022). 2022. ↩︎
Giaume et al. Astroglial connexins and pannexins in CNS disease (2021). 2021. ↩︎