Various types of heteroreceptors and their role in neuroinflammation
| Heteroreceptor complexes | Structure and mechanism | Neuroinflammatory role | Associated disorders | References |
|---|---|---|---|---|
| A2A-D2 (adenosine-dopamine) | The A2A receptor (GPCR) forms heteromeric complexes with the D2 receptor, leading to an antagonistic interaction where A2A activation inhibits D2 signaling. | Enhances neuroinflammation by inhibiting dopaminergic neurotransmission, leading to microglial activation and neurodegeneration. | Parkinson’s disease, Huntington’s disease | [106] |
| 5-HT2A-D2 (serotonin-dopamine) | Interaction between serotonin 5-HT2A and dopamine D2 receptors modulates dopaminergic neurotransmission and immune signaling. | Dysregulation contributes to aberrant dopamine signaling, leading to heightened neuroinflammatory responses in psychiatric disorders. | Schizophrenia, depression, and bipolar disorder | [107] |
| D2-NMDA (dopamine-glutamate) | Dopamine D2 receptors modulate NMDA receptor function, affecting excitatory neurotransmission and synaptic plasticity. | Dysregulation leads to excessive glutamate excitotoxicity, oxidative stress, and chronic neuroinflammation. | Alzheimer’s disease, schizophrenia, stroke | [30] |
| CB1-D2 (cannabinoid-dopamine) | CB1 cannabinoid receptors interact with D2 dopamine receptors to regulate inflammatory and neuroprotective pathways. | Impairment of CB1-D2 signaling contributes to excessive immune activation, neuroinflammation, and neurodegenerative processes. | Multiple sclerosis, neuroinflammation, anxiety disorders | [108] |
| mGluR5-D2 (metabotropic glutamate-dopamine) | mGluR5 modulates D2 receptor activity, influencing synaptic plasticity and neuroimmune responses. | Aberrant crosstalk leads to excitotoxicity, oxidative stress, and neuroinflammatory damage. | Autism spectrum disorder, schizophrenia, epilepsy | [109] |
| TrkB-NMDA (tropomyosin receptor kinase B-glutamate) | TrkB, activated by BDNF, interacts with NMDA receptors to regulate synaptic strength and neuroprotection. | Dysregulation results in impaired neurotrophic signaling, increased oxidative stress, and inflammatory responses. | Major depressive disorder, Alzheimer’s disease | [110] |
| P2X7-NMDA (Purinoceptor-Glutamate) | P2X7 receptor, an ATP-gated ion channel, modulates NMDA receptor activity and glial cell function. | Overactivation leads to excessive calcium influx, neuronal death, and chronic neuroinflammation. | Multiple sclerosis, Amyotrophic lateral sclerosis (ALS) | [111] |
| α7nAChR-NMDA (nicotinic acetylcholine-glutamate) | Nicotinic α7 receptor modulates NMDA receptor-mediated synaptic transmission and anti-inflammatory responses. | Dysregulation results in impaired cholinergic anti-inflammatory signaling and neurotoxicity. | Alzheimer’s disease, schizophrenia, Parkinson’s disease | [112] |
| CXCR4-CCR5 (chemokine receptors) | CXCR4 and CCR5 heterodimerization regulate neuroimmune signaling and leukocyte infiltration in the CNS. | Hyperactivation promotes neuroinflammatory cascades, contributing to neuronal damage. | HIV-associated neurocognitive disorder, multiple sclerosis | [113] |
| GPR37-D2 (G-protein coupled receptor 37-dopamine) | GPR37 interacts with D2 receptors, modulating dopaminergic transmission and neuroinflammation. | Dysfunction contributes to dopaminergic neurodegeneration and inflammatory signaling. | Parkinson’s disease, schizophrenia | [114] |
GPCRs: G-protein-coupled receptors; NMDA: N-methyl-D-aspartate; BDNF: brain-derived neurotrophic factor; CNs: central nervous system
