ICEDlfi 1L

amp1 o ramp2 ramp3

I HIIIIII I

T TTTTTTT. T

Figure 152 Assembly, transport and schematic view of the CGRP receptor complexes. RCP: receptor component protein.

Table 16 Effect of chaperone proteins on the cell surface expression and pharmacological profile of GPCRs. Reprinted from Cellular Signalling, 14, Brady, A. E. and Limbird, L. E., G protein-coupled receptor interacting proteins: Emerging roles in localization and signal transduction, 297-309. Copyright (2002), with permission from Elsevier.

Table 16 Effect of chaperone proteins on the cell surface expression and pharmacological profile of GPCRs. Reprinted from Cellular Signalling, 14, Brady, A. E. and Limbird, L. E., G protein-coupled receptor interacting proteins: Emerging roles in localization and signal transduction, 297-309. Copyright (2002), with permission from Elsevier.

GPCR-chaperone interactions

Functional role(s) implicated

Rhodopsin (Rh1)

nina A (Drosophila)

Rh1 transport to surface of R1-6 photoreceptor

cells

OdrlO (C. elegans)

Odr4 (C. elegans)

Transport Odr 10 to surface of C. elegans

olfactory cilia

rFSH, rLH receptor

Calnexin

Detected in endoplasmic reticulum

V2 receptor

Calnexin

Overexpression of calnexin slows delivery

of WT-V2 receptor to surface; interaction

appears to account for intracellular

accumulation of V2 receptor alleles

responsible for X-linked nephrogenic diabetes

CRLR

RAMP1

Creates CGRP receptor at cell surface capable

of stimulating cAMP generation

CRLR

RAMP2

Creates adrenomedullin receptor at cell surface

capable of stimulating cAMP generation

heterodimers in the endoplasmic reticulum and golgi apparatus. These complexes are maintained during the process of translocation to the cell surface, agonist activation, internalization and lysosomal degradation. Olfactory receptors are another example of GPCR requiring a chaperone for proper cell surface expression (Table 16). Considerable biological diversity may arise when cells and tissues can exhibit differential pharmacological profiles based on the expression pattern of accessory proteins such as RAMPs.

Finally, RAMPs are also essential for terminal CRLR glycosylation, but this process does not seem to affect the recognition properties of the receptor.

Recent studies (McLatchie et al., 1998) revealed the occurrence of four additional family B GPCRs that also bring RAMPs to the cell surface. VPAC1, the vasoactive intestinal polypeptide/pituitary adenylate cyclase-activating peptide receptor, interacts with all three RAMPs. The glucagon receptor and the PTH1 parathyroid hormone receptor interact with RAMP2 and the PTH2 receptor interacts with RAMP3. Accordingly, a number of family B receptors may represent 'core subunits' that interact with RAMPs to produce physiologically relevant receptors. On the other hand, there are receptors within this family (such as CRF receptors) that have not been linked to a RAMP protein.

Other membrane proteins may affect the GPCR-G protein interaction. An interesting example is the D1 dopamine receptor, which is routinely considered to stimulate cAMP production by activating Gs. However, a large increase in Ca2+ concentration is also obtained in the presence of calcyon (a glycosylated 24 kDa single TM protein that

Caveola

DGIWKASFTTFTVTKYWFYR scaffolding domain

<t> X <fc XXXX <t> XX 4> caveolin binding sequence motif

DGIWKASFTTFTVTKYWFYR scaffolding domain

<t> X <fc XXXX <t> XX 4> caveolin binding sequence motif

Figure 153 Structure of caveolae, caveolin and the caveolin binding sequence motif of other proteins (X = any amino acid; O = Phe, Trp or Tyr) (Okamoto et al., 1998, reproduced by permission for the American Society for Biochemistry and Molecular Biology).

interacts within a 16 amino acid segment of the C-terminal tail of the Dj receptor). Calcyon is believed to increase the affinity of the D1 receptor for Gq/11.

The integral membrane protein caveolin forms an oligomeric coat structure around the bulb of caveolae (i.e. cholesterol-containing 50-100 nm 'flask-shaped' invaginations of the plasma membrane) (Figure 153). It spans the membrane twice and is capable of binding GPCRs (via a consensus site such as Tyr302-Tyr312 of the AT1 angiotensin receptor) and other different proteins that are involved in cell signalling. Therefore, it can serve as a scaffold and bring GPCRs in close proximity to other signalling pathways. This topic will be further discussed in Section 4.10.

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