Intramembrane receptor-receptor interactions via heteromerization
| Type of Receptors Involved | Possible Mechanism for Interaction | Changes at Recognition Level | Changes at Signaling Level | Changes in Receptor Trafficking | Possible Therapeutic Implications |
|---|---|---|---|---|---|
| GABABR1/GABABR2 | Coiled-coil interaction at COOH terminus (heterodimers are preferred) | Increased potency of agonists (R1, R2) | Essential for signaling (R1, R2) | Essential for cell surface expression (R1) | Anticonvulsive therapy |
| δ opioid/κ opioid | Direct interaction (heterodimers are preferred) | High affinity for unselective ligands | Synergistic activation of MAPK | Reduced δ R internalization | Pain relief, drug dependence |
| δ opioid/μ opioid | Direct interaction (heterodimers are preferred) | Increased affinity for certain enk peptides | Altered selection of G protein (e.g., Gz) | Unknown | Pain relief, drug dependence |
| 5-HT1B/5-HT1D | Direct interaction (heterodimers are preferred) | Unknown | Unknown | Unknown | Antidepressant treatment |
| D2/D3 | Direct interaction | No clear-cut changes | Increased coupling of D3 to AC | Unknown | Antipsychotic treatment |
| SSTR5/SSTR1 | Direct interaction | Up-regulation of SSTR1 agonist binding | Sensitization of SSTR1 after SSTR5 activation | Unknown | Unknown |
| SSTR5/D2 | Agonist-dependent direct interaction | Positive reciprocal affinity regulation | Enhancement of signaling | Unknown | Antiparkinsonian treatment |
| A1/D1 | Agonist regulation of heteromerization: ADA dependency | Disappearance of D1-R high affinity state | Desensitization of D1-R after A1/D1 agonist treatment | A1-induced coaggregation of A1-R/D1-R | Antiparkinsonian treatment drug dependence |
| mGLU-R1α/A1 | Involvement of mGLU-R1α COOH terminus: Homer dependency? | Unknown | Reciprocal enhancement of Ca2+ signaling | Unknown | Neuroprotection |
| P2Y1/A1 | Direct interaction | Novel A1-R binding pocket? | Altered selection of G protein | Unknown | Neuroprotection |
| A2A/D2 | Possible involvement of D2 5,6 TM domains and intracellular loop 3 | Reduced D2-R affinity, especially high-affinity state | Reduced D2-R Ca2+ and cAMP signaling | Coaggregation, cointernalization, codesensitization | Antiparkinsonian, antipsychotic, antidyskinetic treatment |
| A2A/mGLU-R5 | Homer dependency? | Unknown | Synergism for c-Fos expression | Unknown | Antiparkinsonian, antipsychotic, antidyskinetic drug dependence treatment |
| B2/AT1 | Unknown (no adapter proteins) | Complex regulation of AT1-R affinity | Increase in AT1-R coupling to G protein | Altered receptor trafficking | Antihypertensive treatment |
| D5/GABAA | COOH-terminal γ2 intracellular loop 2, (agonist coactivation-dependent) | No changes in D5-R binding | Reduction of GABAA-dependent currents and of D5-R signaling | Agonist induced contrafficking | Antipsychotic treatment |
| β2/EGF-R | Multiprotein complex (involvement of β-arrestin) agonist dependency | Unknown | Transactivation of EGF-R | Favoring of clathrinmediated endocytosis | Neuroprotection, neuroplasticity |