Opinion
Cocaine affects the dynamics of cytoskeletal proteins via sigma1 receptors

https://doi.org/10.1016/S0165-6147(00)01740-5Get rights and content

Abstract

Cytoskeletal proteins are important in protein trafficking, membrane protein clustering, dendrite growth and the morphological maintenance of neurons. Sigma1 receptors are unique endoplasmic reticular (ER) proteins that bind (+)benzomorphans, neurosteroids and psychotropic drugs such as cocaine. Cocaine, via sigma1 receptors, can cause the dissociation of a cytoskeletal adaptor protein ankyrin from inositol (1,4,5)-trisphosphate [Ins(1,4,5)P3] receptors on the ER as a sigma1-receptor–ankyrin complex, which then translocates to the plasma membrane and nucleus. The dissociation of sigma1-receptor–ankyrin from Ins(1,4,5)P3 receptors also increases the intracellular Ca2+ concentration {[Ca2+]i}, which affects the activity of cytoskeletal proteins. Furthermore, cocaine might increase [Ca2+]i via phospholipase C (PLC)-linked dopamine D1 receptors. We hypothesize that cocaine might cause life-long changes in neurons via cytoskeletal proteins by interacting with both D1 receptors and sigma1 receptors.

Section snippets

Interaction with sigma1 receptors

Now, it is known that sigma1 receptors and associated ligands, including cocaine and neurosteroids, can affect Ca2+ signaling at the ER in NG-108 cells 12 by causing the dissociation of a cytoskeletal adaptor protein ankyrin (specifically the ANK220 isomer) from the inositol (1,4,5)-trisphosphate [Ins(1,4,5)P3] receptors on the ER (Ref. 2) (Fig. 1). Ankyrins are proteins that interconnect spectrin-based cytoskeletons to membrane proteins and cell adhesion molecules, thus playing important roles

The role of Ca2+ in the life-long effects of cocaine

It is well known that [Ca2+]i plays important roles in cell differentiation and proliferation, and in the activation of transcription factors. Thus, although we hypothesize that cytoskeletal proteins might play important roles in the life-long action of cocaine, it is possible that Ca2+ might also play an important role in these effects. Indeed, [Ca2+]i can, via the activation of kinases 13, change the intrinsic activity and organization of cytoskeletal proteins, which suggests that a

Chemical name

NE100N,N-dipropyl-2-[4-methoxy-3-(2-phenylethoxy)phenyl]-ethylamine monohydrochloride

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