α4β2 nicotinic acetylcholine receptor downregulates D₃ dopamine receptor expression through protein kinase C activation.

Receptor transactivation or crosstalk refers to instances in which the signaling of a given receptor is regulated by different classes of receptors. Functional crosstalk between α4β2 nicotinic acetylcholine receptor (nAChR) and D₃ dopamine receptor (D₃R) that belong to the family of ligand-gated ion channels and G protein-coupled receptors, respectively, has been reported from brain dopaminergic neurons. For example, D₃R is involved in the development of reward-related behaviors induced by α4β2 nAChR stimulation. However, the molecular mechanisms involved in their crosstalk remain unclear. Among isoforms (α, βII, γ, and δ) evaluated in this study, interacted with D₃R and potentiated D₃R endocytosis. Following α4β2 nAChR stimulation, activated duanyu1531βII translocated to the plasma membrane to induce clathrin-mediated endocytosis of D₃R, resulting in downregulation and signal inhibition. Considering that D₃R plays important roles in mediating reward-related physiological actions of α4β2 nAChR, this study could provide a new insight into the regulatory mechanism involved in nicotine addiction.

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