Abstract
The amino acid sequences of the human (h) and rat (r) follitropin receptors (FSHR) are approximately 89% identical, but the half-time of internalization of agonist mediated by the rFSHR is approximately 3 times faster than that of the hFSHR. Chimeras of the hFSHR and the rFSHR showed that this difference in rate is dictated mostly by the serpentine domain. Further analysis identified six residues, two non-contiguous residues in the transmembrane helix 4 (Leu/Thr in the rFSHR and Met/Ile in the hFSHR), three non-contiguous residues in the third intracellular loop (Thr/Thr/Lys in the rFSHR and Ile/Asn/Arg in the hFSHR), and one in transmembrane helix 7 (Tyr in the rFSHR and His in the hFSHR) that are fully responsible for the difference in the rates of internalization of the hFSHR and the rFSHR.
Highlights
Like many other GPCRs, the agonist-induced activation of the glycoprotein hormone receptors results in the internalization of the agonist-receptor complex via clathrin-coated pits [10, 11] by a pathway that requires dynamin [12,13,14,15,16,17]
The GPCRs that are internalized by this pathway are targeted to clathrin-coated pits via adaptor proteins such as the non-visual arrestins [31, 32, 34], and the fission of the coated pits into coated vesicles requires the participation of dynamin [35]
Since the agonist-induced internalization of the LHR and the FSHR are sensitive to inhibition by dominant-negative mutants of dynamin or by dominant-negative mutants of the non-visual arrestins [13, 15,16,17, 26], we can readily conclude that they are internalized by the same, non-visual arrestin and dynamin-sensitive pathway
Summary
Like many other GPCRs, the agonist-induced activation of the glycoprotein hormone receptors results in the internalization of the agonist-receptor complex via clathrin-coated pits [10, 11] by a pathway that requires dynamin [12,13,14,15,16,17]. The agonist-induced activation and phosphorylation of these receptors as well as their interaction with a non-visual arrestin can be readily recognized as important steps in agonist-induced internalization [12,13,14,15,16,17] In addition to these common properties of their internalization pathways, the glycoprotein hormone receptors display some interesting differences. The internalized rodent or porcine LHR are routed to the lysosomes [10, 11, 18], whereas the internalized human TSHR is routed to a recycling pathway [11] Recent studies from this [15, 17] and other laboratories [11] took advantage of the high amino acid sequence homology among the glycoprotein hormone receptors to begin to understand the structural features of these receptors that participate in internalization and trafficking. There is no overlap in the identity of the residues that dictate the internalization of the LHR and the FSHR, and there is little overlap in the topological location of these residues
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