Table 2.
Major GPCRs in brain ECs
| Gene | Ligands | Gα subunits | Notes | Ref |
|---|---|---|---|---|
| Sphingosine 1-phospate receptors (S1PR) | ||||
| S1PR1 | Sphingosine 1–phosphate | i/o | Endothelial specific S1pr1−/− mice have loosened BBB with altered CLDN-5 localization | [65] |
| S1PR2 | 12/13 | Its expression was induced by hypoxic stress in the ECs for promoting angiogenesis. | [112] | |
| S1PR4 | i/o, 12/13 | Selective S1PR4 antagonist (CYM50358) could loosen the BBB in mice | [66] | |
| Frizzled receptors (FZDs) | ||||
| GPR124 | Wnt7a/b | - | There is an atypical Wnt7a/b-specific co-receptor complex with Reck/GPR124/FZDs in brain ECs to stabilize the TJs | [73] |
| Lysophosphatidic acid (LPA) receptors | ||||
| LPAR4 | 18:1 LPA | s, i/o, q/11, 12/13 | Lpar4−/− mice show attenuated LPA-induced hypertensive response in a Gα12/13 dependent manner. | [111] |
| LPAR6 | 2-acyl-LPA | 12/13 | Lpar6−/− mice have a decreased vascular density and branching and show attenuated LPA-induced hypertensive response | [111] |
| Receptors for metabolic waste products | ||||
| GPR4 | CO2/H+ | q/11, s, i/o, 12/13 | Gαq/11 is used for CO2-mediated vasodilation. Gαs activation is also reported. | [131] |
| HCAR1 | Lactate | i/o | It is expressed in both luminal and abluminal side. | [71] |
| Receptors for prostaglandins (PGs) | ||||
| PTGER1 | PGE2 | q/11 | Responsible PGE2 receptor for vasodilation via PGE2 released from activated CNS cells | [116] |
| PTGER2, 4 | PGE2 | s | Its expression in brain ECs was induced by ischemia-reperfusion injury. | [107] |
| Other important GPCRs in the BBB | ||||
| CALCRL | Adrenomedulin | s | Fluid shear stress-induced Piezo-1 activation induces adrenomedullin. | [104] |
| P2RY1, 2 | ATP | q/11 |
Fluid shear stress-induced Piezo-1 activation induces ATP. Activated CNS cells also release ATP. |
[106] |
| ADORA2A | Adenosine | s | Adenosine mainly arises from the hydrolysis of released ATP. | [105] |
| SMO | SHH bound PYCH-1 | i/o | Active Gαi is necessary for efficient activation of Gli transcriptional factors. | [76] |
| F2R | Itself | 12/13, q/11 | A lymphocyte-released serine protease or thrombin can activate it | [113] |
| HRH1 | Histamine | q/11 | Endothelial dysfunction induced by histamine is dependent on Gαq/11 and RhoA | [132] |
| BDKRB2 | Bradykinin | q/11 | RMP-7 bradykinin analog is a representative BBB opener | [133] |
| GPR55 | Lysophosphatidylinositol | q/11, 12/13 | GPR55 is also activated by endocannabinoids and synthetic cannabinoid ligand | [134] |
PTCH-1, patched-1; SHH, Sonic hedgehog;