Journal
LIFE SCIENCES
Volume 82, Issue 13-14, Pages 718-727Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.lfs.2008.01.013
Keywords
muscarinic; endocytosis; small G-proteins; GPCR; trafficking; vesicle
Funding
- NHLBI NIH HHS [P01 HL044948, P01 HL044948-120008, HL44948] Funding Source: Medline
- NIGMS NIH HHS [T32 GM007750, GM07750] Funding Source: Medline
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, Multiple mechanisms exist for the endocytosis of receptors from the cell surface. While the M-1, M-3, and M-4 subtypes of muscarinic acetylcholine receptors internalize through the well-characterized mechanism of clathrin coated vesicles, the mechanism Of M-2 endocytosis is not well defined. Because the M-2 and M-4 receptors transduce their signals through the same second messengers but internalize though different pathways, we tested the ability of several small G-proteins to regulate the agonist-induced endocytosis Of M-2 and M-4 in JEG-3 human choriocarcinoma cells. Dominant-negative Rab5 as well as both wild-type and dominant-negative Rab11 inhibited M-4 but not M-2 endocytosis. In contrast, a dominant-negative Arf6 as well as wild-type Rab22 increased M-2 but not M-4 endocytosis. We used immunocytochemistry to show that in unstimulated cells, the M-2 and M-4 receptors co-localize on the cell surface, whereas after stimulation M-2 and M-4 are in distinct vesicular compartments. In this study, we demonstrate that agonist-induced internalization of the M-2 receptor utilizes an Arf6, Rab22 dependent pathway, while the M-4 receptor undergoes agonist-induced internalization through a Rab5, Rab11 dependent pathway. Additionally, we show that Rab15 and RhoA are not involved in either pathway in JEG-3 cells. (c) 2008 Elsevier Inc. All rights reserved.
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