The CB1 cannabinoid receptor C-terminus regulates receptor desensitization in autaptic hippocampal neurones
Article first published online: 23 MAR 2012
© 2011 The Authors. British Journal of Pharmacology © 2011 The British Pharmacological Society
British Journal of Pharmacology
Special Issue: Themed Section: Cannabinoids in Biology and Medicine, Part II. Guest Editors: Itai Bab and Steve Alexander
Volume 165, Issue 8, pages 2652–2659, April 2012
How to Cite
Straiker, A., Wager-Miller, J. and Mackie, K. (2012), The CB1 cannabinoid receptor C-terminus regulates receptor desensitization in autaptic hippocampal neurones. British Journal of Pharmacology, 165: 2652–2659. doi: 10.1111/j.1476-5381.2011.01743.x
- Issue published online: 23 MAR 2012
- Article first published online: 23 MAR 2012
- Accepted manuscript online: 20 OCT 2011 10:29AM EST
- Received; 30 November 2010; Revised; 5 September 2011; Accepted; 15 September 2011
- retrograde transmission
BACKGROUND AND PURPOSE The cannabinoid CB1 receptor is the chief mediator of the CNS effects of cannabinoids. In cell culture model systems, CB1 receptors both desensitize and internalize on activation. Previous work suggests that the extreme carboxy-terminus of this receptor regulates internalization via phosphorylation of residues clustered within this region. Mutational analysis of the carboxy-terminus of CB1 receptors has demonstrated that the last six serine/threonine residues are necessary for agonist-induced internalization. However, the structural determinants of CB1 receptor internalization are also dependent on the local cellular environment. The importance of cell context on CB1 receptor function calls for an investigation of the functional roles of these residues in neurones.
EXPERIMENTAL APPROACH To determine the structural requirements of CB1 internalization in neurones, we evaluated the signalling properties of carboxy-terminal mutated CB1 receptors expressed in cultured autaptic hippocampal neurones, using electrophysiological methods.
KEY RESULTS CB1 receptors transfected into CB1 knockout neurones signalled and desensitized as did wild-type neurones, allowing us to test specific CB1 receptor mutations. Deletion of the last 13 residues yielded a CB1 receptor that inhibited excitatory postsynaptic currents but did not desensitize. Furthermore, mutation of the final six serine and threonine residues to alanines resulted in a non-desensitizing receptor. In contrast, CB1 receptors lacking residues 419–460, leaving the last 14 residues intact, did desensitize.
CONCLUSIONS AND IMPLICATIONS The distal thirteen residues of CB1 receptors are crucial for their desensitization in cultured neurones. Furthermore, this desensitization is likely to follow phosphorylation of serines and threonines within this region.
LINKED ARTICLES This article is part of a themed section on Cannabinoids in Biology and Medicine. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2012.165.issue-8. To view Part I of Cannabinoids in Biology and Medicine visit http://dx.doi.org/10.1111/bph.2011.163.issue-7