The corticotropin releasing factor (CRF) receptors belong to the large family of G proteincoupled
receptors (GPCRs) and must be transported to the plasma membrane to function properly. The
first step of the intracellular transport of GPCRs is their insertion into the membrane of the endoplasmic
reticulum (ER). This process is mediated by the translocon complex of the ER membrane and the signal
sequences of the receptors. Most GPCRs possess signal sequences which form part of the mature proteins,
the so called signal anchor sequences (usually transmembrane domain 1). The CRF receptors possess
instead signal sequences at their extreme N tails which were thought to be cleaved off following
integration of the receptors into the ER membrane (signal peptides, SPs, also called cleaved signal sequences).
Recent work, however, showed that not all subtypes of CRF receptors stick to this rule.
Whereas the corticotropin-releasing factor receptor type 1 (CRF1R) and the corticotropin-releasing factor
receptor type 2b (CRF2(b)R) possess conventional SPs which are indeed cleaved off following ER
insertion, the SP of the cortictropin-releasing factor receptor type 2a (CRF2(a)R) remains uncleaved. It
forms a unique N-terminal domain (pseudo signal peptide, PSP) which has surprising functions beyond
the ER level. Its presence not only influences expression levels at the plasma membrane but also receptor
homodimerisation and, as a consequence, G protein selectivity. In this mini-review, we summarize
the progress in understanding the functions of SPs of CRF receptors. Recent data also allow deriving
hypotheses for a physiological significance of these sequences.