The N-terminal region of the dopamine D2 receptor, a rhodopsin-like GPCR, regulates correct integration into the plasma membrane and endocytic routes.

BACKGROUND AND PURPOSE: Functional roles of the N-terminal region of rhodopsin-like GPCR family remain unclear. Using dopamine D(2) and D(3) receptors as a model system, we probed the roles of the N-terminal region in the signalling, intracellular trafficking of receptor proteins, and explored the critical factors that determine the functionality of the N-terminal region. EXPERIMENTAL APPROACH: The N-terminal region of the D(2) receptor was gradually shortened or switched with that of the D(3) receptor or a non-specific sequence (FLAG), or potential N-terminal glycosylation sites were mutated. Effects of these manipulations on surface expression, internalization, post-endocytic behaviours and signalling were determined. KEY RESULTS: Shortening the N-terminal region of the D(2) receptor enhanced receptor internalization and impaired surface expression and signalling; ligand binding, desensitization and down-regulation were not affected but their association with a particular microdomain, caveolae, was disrupted. Replacement of critical residues within the N-terminal region with the FLAG epitope failed to restore surface expression but partially restored the altered internalization and signalling. When the N-terminal regions were switched between D(2) and D(3) receptors, cell surface expression pattern of each receptor was switched. Mutations of potential N-terminal glycosylation sites inhibited surface expression but enhanced internalization of D(2) receptors. CONCLUSIONS AND IMPLICATIONS: Shortening of N-terminus or mutation of glycosylation sites located within the N-terminus enhanced receptor internalization but impaired the surface expression of D(2) receptors. The N-terminal region of the D(2) receptor, in a sequence-specific manner, controls the receptor's conformation and integration into the plasma membrane, which determine its subcellular localization, intracellular trafficking and signalling properties.

Evaluation of design parameters of osseointegrated dental implants using finite element analysis.

Finite element analyses were performed for various shapes of dental implant to study effects on stress distribution generated in the surrounding jaw bone and to determine an optimal thread shape for even stress distribution. It was found that the square thread shape filleted with a small radius was more effective on stress distribution than other dental implants used in the analyses. Additional analyses were performed on the implant with the thread shape obtained from previous analyses for varying other design parameters, such as the width of thread end and height of thread for various load directions, to determine the optimal dimensions of the implant. Stress distribution was more effective in the case when the width of thread end and the height of thread were 0.5p and 0.46p, respectively, where p is the screw pitch. Then, using the optimal implant thread dimensions determined previously, stress analyses were performed with various screw pitches and implant lengths, to investigate effects on stress distribution and to find the way to reduce the maximum effective stress generated in the jaw bone. Results show that the maximum effective stress decreased not only as screw pitch decreased gradually but also as implant length increased.