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 alpha 4 beta 2 nicotinic acetylcholine receptor (nAChR) and D-3 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 alpha 4 beta 2 nAChR stimulation. However, the molecular mechanisms involved in their crosstalk remain unclear. Among PKC isoforms (alpha, beta II, gamma, and delta) evaluated in this study, PKC beta II interacted with D3R and potentiated D3R endocytosis. Following alpha 4 beta 2 nAChR stimulation, activated PKC beta II 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 alpha 4 beta 2 nAChR, this study could provide a new insight into the regulatory mechanism involved in nicotine addiction. (C) 2019 Elsevier Inc. All rights reserved.