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RACK1 inhibitors reveal PKC gamma and epsilon in mediating morphine tolerance
Author(s) -
Smith Forrest L.,
Smith Paul A.,
Dewey William L.
Publication year - 2006
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.20.4.a239-c
Subject(s) - protein kinase c , microbiology and biotechnology , nmda receptor , chemistry , phosphorylation , receptor , biology , pharmacology , biochemistry
The process of translocation of PKC from the cytosol to membranes is tightly regulated by RACK1 anchoring proteins, defined as Receptors for Activated C Kinase (RACK). The amino acid sequence allows for only a specific PKC isoform to undergo active translocation to that site, allowing for the phosphorylation of specific target proteins with the addition of appropriate co‐factors such as diacylglycerol, phosphatidylserine, and calcium (with conventional PKC isoforms). To date the RACKs for PKC betaI, betaII, gamma, delta, theta, epsilon and eta have been developed for research purposes. Swiss‐Webster mice implanted with placebo or 75 mg morphine pellets developed significant tolerance 3‐days later in the 56 °C tail‐withdrawal and hot‐plate tests, and tolerance to morphine‐induced hypothermia. Pretreatment i.c.v. with RACK1 inhibitor to PKC betaI, betaII, delta, theta and eta all failed to significantly reverse morphine tolerance in any of these tests. However, the RACK1 inhibitors to PKC gamma and epsilon significantly reversed tolerance in each of the tests. PKC epsilon has been located predominantly on primary afferent neurons on pre‐synaptic terminals in the spinal cord, while PKC gamma is located on postsynaptic sites associated with glutamate release and the activation of NMDA receptors. PKC alpha translocates to F‐actin, and therefore does not have a specific RACK1 site. However, PKC alpha has also been implicated in morphine tolerance. These data demonstrate that PKC gamma and epsilon must undergo active translocation in order to mediate morphine tolerance. Funded by NIDA grants: R01‐DA‐01647, T32‐DA‐0027, K05‐DA‐00480.