N-Terminal Signal Peptides of G Protein-Coupled Receptors: Significance for Receptor Biosynthesis, Trafficking, and Signal Transduction

Signal sequences play a key role during the first steps of the intracellular transport of G protein-coupled receptors (GPCRs). They are involved in targeting of the nascent chains to the membrane of the endoplasmic reticulum (ER) and initiate integration of the newly synthesized receptors into this compartment. Two classes of signal sequences are known: N-terminal signal peptides, which are usually cleaved-off following ER insertion and internal signal sequences, the so-called signal anchor sequences, which form part of the mature proteins. About 5-10% of the GPCRs contain N-terminal signal peptides; the vast majority possesses signal anchor sequences. The reason why only a subset of GPCRs require signal peptides for ER targeting/insertion was addressed in the past decade by a limited number of studies indicating that the presence of signal peptides facilitates N-tail translocation at the ER membrane. Interestingly, recent work showed that signal peptides of GPCRs do not only serve "classical" functions in the early secretory pathway. Uncleaved pseudo signal peptides may regulate receptor densities in the plasma membrane, receptor dimerization, and G protein coupling selectivity. On the other hand, even cleaved and released peptides may have post-ER functions. In this review, we summarize the current knowledge about cleavable signal peptides of GPCRs and address also the question whether these sequences may serve as future drug targets in pharmacology.