Fig. 8.
The endothelium-dependent hyperpolarization microdomain. The EDH response starts with the activation of IP3R at the ER in EC by a GqPCR [for example, muscarinic (M3), BK, or the calcium sensing receptor (CaR)]. The calcium released from the ER activates the calcium-sensitive potassium channels SKCa at the EC-EC junctions and IKCa at the MEJ, which induces hyperpolarization of the EC. In parallel, the calcium release from the ER activates the capacitive entry of calcium at both the EC-EC junctions and the MEJ via TRPV4 channels, which sustains the opening of the IKCa and SKCa channels. The activation of SKCa and IKCa at the plasma membrane of ECs activates the efflux of potassium and its accumulation in the extracellular space between the VSMCs and the ECs. This potassium accumulation further activates the sodium/potassium ATPase (Na/K/ATPase) at the plasma membrane of VSMC, producing hyperpolarization and relaxation of the VSMC by closing the voltage-gated calcium channels (VGCC). The hyperpolarization of EC can also be transferred to the adjacent ECs and VSMCs via gap junctions channels located at the MEJ and at the EC-EC junctions. Wavy arrows indicate hyperpolarization.