How Relevant Are Heterodimers as Disease Targets

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It is now well accepted that many GPCRs can exist as homo- and heterodimers. However, the physiologic relevance of receptor dimerization is still largely unknown. It is clear from some studies that GPCR dimerization can alter ligand function; for example, a number of anti-parkinsonian agents have been reported to have a higher affinity with dopamine D3/D2 heterodimers than with the equivalent homodimers (31). Another example is provided by the receptors CB1 (cannabinoid) and orexin. When these are coexpressed, CBj enhances the ability of orexin A to activate the mitogen-activated protein (MAP) kinase pathway (32). This effect requires a functional CB1 receptor and is blocked by the specific antagonist rimonabant. Further studies have shown that the orexin receptor and the CB1 receptor form heterodimers and that the appetite suppression effect of the CB1 antagonist rimonabant targets this complex (G. Milligan, personal communication). This is a classic example of GPCR het-erodimers playing a role in physiology. Drug discovery will obviously have to pay very careful attention to heterodimeric complexes of GPCRs.

An intriguing report by McGraw et al. demonstrates that even quite unrelated receptors can form heterodimers (33). The authors reasoned that the successful response of asthmatics to p2-adrenergic receptor agonists might involve GPCR interactions. They followed up on this idea by looking at the signaling of the prostanoid EP1 receptor, because its endogenous agonist PGE2 is abundant in the airway, but its functional implications are poorly defined. Although activation of EP1 failed to elicit airway smooth muscle contraction by itself, it did significantly reduce the bronchodilatory function of a p2-adrenergic receptor agonist. Using bioluminescence resonance energy transfer (BRET), the authors demonstrated that EP1 and p2-adrenergic receptor formed heterodimers that were responsive to an EP1 agonist.

There is already a large literature establishing that chemokine receptors can form hetero- and homodimers. For example, CCR5 has been shown to form homo- and heterodimers with CCR2, a closely related receptor (34). This dimerization appears to be induced by the CCR2 ligand CCL2. A recent study reveals that CCR5 and CCR2 heterodimerize with the same efficiency as they homodimerize (35). Interestingly CCL4, a CCR5-specific ligand that was unable to compete for CCL2 binding on cells expressing CCR2 alone, efficiently inhibited CCL2 binding when CCR5 and CCR2 were coexpressed (35). These findings suggest that CCR5 and CCR2 can form both homo- and heterodimers with similar efficiencies and that a receptor dimer only binds a single chemo-kine. Finally, another report suggests that a specific CCR5 antibody blocks HIV-1 replication in vitro as well as in vivo (36). The antibody does not induce receptor downregulation or compete with chemokine binding and signaling on the receptor or interfere with the R5 JRFL viral strain gp120 binding to CCR5. It appears that the anti-CCR5 antibody efficiently prevents HIV-1 infection by inducing receptor dimerization. These findings suggest that it might be possible to develop new and interesting therapeutics that target the ability of chemokine receptors to dimerize without having any of the undesired proinflammatory side effects of the chemokines themselves.

Not all of the reports of chemokine dimerization are consistent, however, and whereas some studies have reported that CXCL12 induces dimerization of CXCR4 that is almost undetectable in the absence of the ligand (37), others have suggested that CXCR4 is a constitutive dimer not affected by the CXCL12 (38). Finally, even highly related chemokine receptors such as CXCR1 and CXCR2 that both bind CXCL8 with high affinity appear to show very different patterns of dimerization. For example, studies that clearly revealed the ligand-independent dimerization of CXCR2 also reported that CXCR1 did not dimerize (39). However, these findings have recently been challenged by a study that used a combination of coimmunoprecipitation, saturation BRET, and a novel endoplasmic reticulum-trapping strategy (40). In this study, the authors were able to demonstrate that CXCR1 is able to form both homo- and heterodimers with CXCR2.

Although we do not currently understand the physiologic consequences of receptor homo- and heterodimerization, the examples discussed above suggest that such receptor interactions may have important functional consequences. These receptor interactions can clearly affect surface expression of receptors, rates of receptor desensitization, and the pharmacology of ligands for the receptor. The clinical significance of these findings is just now being appreciated. For example, it is clear from the discussion above that the ability of chemokine receptors to act as coreceptors for the HIV virus is directly influenced by receptor heterodimerization. In line with this idea, a polymorphism (V64I) in the chemo-kine receptor CCR2 has been found to correlate with a markedly decreased rate of AIDS progression (41). The V64I CCR2 polymorphism has also been shown to enhance heterodimerization between CCR2/CCR5 and CCR2/CXCR4 (42). These findings suggest that heterodimerization of chemokine receptors is a key determinant in the ability of HIV to use these receptors to gain entry into cells, and it might suggest a new avenue of therapeutic intervention in the future.

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Coping with Asthma

Coping with Asthma

If you suffer with asthma, you will no doubt be familiar with the uncomfortable sensations as your bronchial tubes begin to narrow and your muscles around them start to tighten. A sticky mucus known as phlegm begins to produce and increase within your bronchial tubes and you begin to wheeze, cough and struggle to breathe.

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