Questions to Consider for Future Investigations

This review provides examples of the roles of membrane rafts and caveolae in the organization and regulation of signal transduction, especially by GPCR. In spite of considerable data that document such roles, a number of unanswered questions remain. These include:

- What is the full range of signaling proteins and signaling cascades that are organized in caveolae and membrane rafts, and do physiological states, drugs or disease alter the identity of these raft/caveolae "partners"?

- What are the mechanisms/interactions that determine co-localization and functional regulation of signaling proteins in those microdomains?

- Is the CSD the only means by which signaling proteins associate with caveolae, and if so, how does this association occur for so many signaling and other proteins?

- Is there a signaling role for cellular pools of caveolins that exist outside of caveo-lae (as reviewed in Head and Insel 2007)?

- Does the compartmentation of GPCR and post-receptor components in caveolae/ rafts contribute to disease manifestations and therapeutic responses in disease?

Investigations that attempt to answer such questions are predicted to reveal new insights into the physiological, pathophysiological and pharmacological role of rafts and caveolae. The answers will likely also reveal insights regarding compartmentation of signal transduction, in particular by GPCR. In addition, the findings may yield novel targets for drug action, such as sites that contribute to the proteinprotein and protein-lipid interactions that appear to be critical for membrane raft and caveolar interaction with protein partners.

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