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E-Conference: Defining Calcium Entry Signals

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What are lipid rafts?

17 June 2004

Indu S. Ambudkar

Lipid rafts:

The idea that lipid rafts are involved in Ca2+ signaling is very appealing and in view of the biochemical data that have been reported it appears that signaling and Ca2+ entry can in fact occur in such microdomains.

However, the methods that have been used to assess protein- association with lipid-raft domains are by no means rigorous. The techniques and reagents used for these studies are fairly non-specific and unless carefully controlled can lead to artifacts.

One such example is the detergent solubilization protocol. Insolubility in Triton-X-100 is not always an indicator of LRD association. Just as detection at the bottom of the gradient does not mean that it is not associated with LRD. The most simplistic case is a protein that is somehow anchored to the cytoskeleton. This interaction will render it insoluble in detergent and cause it to sink to the more dense fractions of the gradient. That itself does not exclude LRD association unless one disrupts the interaction with the cytoskeleton and demonstrates that it either floats to the top or remains in the lower fractions.

Very few people try to use other detergents that are known to disrupt LRDs to show differential solubilization. These experiments are tedious and require meticulous detail. Further, one has to discriminate between lipid rafts in the plasma membrane versus those in the trafficking membranes or golgi.

Regarding the very dynamic nature of the lipids in the rafts, yes this is true. But, there are the relatively “stable” LRDs, such as caveolar lipid raft domains. Another way could be a scaffold that is closely associated with the LRD which can hold the proteins in place.

Thus, although the lipids themselves might be dynamic, the proteins (specifically polytopic plasma membrane proteins) might actually be more stably anchored. The question of course is does the dynamic lipid environment impact on the physiological function of the protein.

Another question I have asked the LRD aficionados is whether such proteins move into LRDs or whether the lipid around the protein changes and in doing so brings other regulatory proteins (e.g. GPI-anchored) or lipids that are associated with the LRD to the protein.

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