Biomedical Engineering Reference
In-Depth Information
New light on the regulated transport of olfactory receptors was shed by genetic
studies in
C. elegans
aimed at characterizing the proteins involved in warm olfaction.
Among the genes coding for the olfactory receptors or for components of the signaling
pathway some genes of previously unknown function were identified. In particular,
odr-4 and odr-8 genes were found to be required for localization of a subset of odorant
receptors to the cilia of olfactory neurons. Odr-4 encodes a single transmembrane
domain (1TM) protein exclusively expressed in chemosensory neurons, which facil-
itates odorant receptor localization at the cell surface (Dwyer et al.
1998
) . At the
same time, a group of 1TM proteins was found to modulate the cell surface export of
GPCRs in mammals (McLatchie et al.
1998
) . These Receptor-Activity-Modifying
Proteins or RAMPs, are required to transport the calcitonin-receptor-like receptor
CRLR to the plasma membrane. In addition, depending on the RAMP, which inter-
acts with CRLR, the binding specificity of the receptor is modified. Thus, both in
C.
elegans
and in mammalian cells the proper cell surface expression of some GPCRs
relies on the interaction with “escort proteins”, which interact with receptors in
intracellular compartments and remain associated with them at the cell surface.
Another piece of the puzzle of the regulated GPCR export was provided by
the discovery of the very peculiar mechanism of the metabotropic GABA
B
receptor
delivery to the plasma membrane of neurons. Indeed, the functional GABA
B
receptor is constituted by hetero-dimers of two receptor isoforms, referred to as
GB1 and GB2 (Jones et al.
1998
; Kaupmann et al.
1998
; White et al.
1998
) .
Although the N-terminus of GB1 contains the GABA binding site (Jones et al.
1998
), heterologous GB1 expressed in primary neuronal cells and most fibroblasts
or epithelial cells is not competent for transducing GABA-dependent signals
(Couve et al.
1998
). The reason for this is that GB1, which contains an arginin-
based ER retention/retrieval signal in its carboxyterminal tail, is retained in the
endoplasmic recticulum (ER) and does not reach the cell surface in the absence
of co-expressed GB2. The shielding of this retention signal via a coiled-coil
interaction with the C-terminus of GB2 may allow the GB1-GB2 hetero-dimer to
progress along the secretory pathway and to reach the cell surface (Margeta-
Mitrovic et al.
2000
) .
An additional argument supporting the existence of physiological mechanisms
regulating GPCR exiting from intracellular retention was the capacity of rescuing
ER-trapped GPCR mutants with specific peptides or pharmacological chaperones
(Schoneberg et al.
1996
; Morello et al.
2000
). More than a dozen of congenital
diseases have been linked to mutations in GPCRs that lead to their retention in
the ER (Bernier et al.
2004
). Although some mutations may cause major folding
problems, which activate the quality control machinery and result in proteasomal
degradation of the unfolded receptors, other mutations induce the accumulation of
receptors in the ER from which they can be released upon binding of membrane
permeable ligands. In the latter case the folding problem causing retention is likely
relatively modest, at least for those GPCR mutants which appear fully functional
once they have reached the cell surface. It might simply reflect a conformational
state enhancing receptor affinity for physiological retention mechanisms controlling
exiting from the ER.
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