Lipid Rafts and Dopamine Receptor Signaling

Abstract

The renal dopaminergic system has been identified as a modulator of sodium balance and blood pressure. According to the Centers for Disease Control and Prevention, in 2018 in the United States, almost half a million deaths included hypertension as a primary or contributing cause. Renal dopamine receptors, members of the G protein-coupled receptor family, are divided in two groups: D1-like receptors that act to keep the blood pressure in the normal range, and D2-like receptors with a variable effect on blood pressure, depending on volume status. The renal dopamine receptor function is regulated, in part, by its expression in microdomains in the plasma membrane. Lipid rafts form platforms within the plasma membrane for the organization and dynamic contact of molecules involved in numerous cellular processes such as ligand binding, membrane sorting, effector specificity, and signal transduction. Understanding all the components of lipid rafts, their interaction with renal dopamine receptors, and their signaling process offers an opportunity to unravel potential treatment targets that could halt the progression of hypertension, chronic kidney disease (CKD), and their complications.

Keywords: G protein; dopamine receptor; lipid rafts; signaling.

Figure 1

Cell membrane partitions into lipid raft and non-lipid raft microdomains.

Figure 2

Caveola structure.

Figure 3

Agonist-induced stimulation of G protein-coupled receptors (GPCRs) (e.g., dopamine receptor (1) and phosphorylation of GDP to GTP on the Gα subunit of the G protein (2)).

Figure 4

Uncoupling of Gα subunit from Gβγ subunit, followed by activation GPCR kinases (GRKs), which phosphorylate amino acids in the third intracellular loop of the transmembrane segments and C-terminal tail (3a). The uncoupled Gα subunit activates downstream cellular (3b) and subsequent cellular response (3c).

Figure 5

The phosphorylation of amino acids in the third intracellular loop of the transmembrane segments and C-terminal tail leads to the activation of β-arrestins (5a).

Figure 6

Dynamin and clathrin associate with the GPCR (dopamine receptor) and mediate its endocytosis by means of the adaptor protein 2 (AP2) (6a).

Figure 7

Endocytosed GPCR (dopamine receptor) is packaged in an early endosome (7a).

Figure 8

The endocytosed GPCR (dopamine receptor) binds to sorting nexin (SNX) that sends the GPCR either to a recycling endosome or lysosome (8a). Receptors targeted to lysosomes are degraded.

Figure 9

The resensitized GPCR (dopamine receptor) is targeted to the lipid raft microdomain by SNX (9a) and is ready to bind to a new agonist (9a).

Figure 10

Structural differences between D1-like receptor (left side of picture) and D2-like receptors (right side of picture).

Figure 11

D1-like receptors are linked to Gαs subunit.

Figure 12

D1-like receptors are linked to Gαq subunit.