Cannabinoid receptor desensitization

Ronken E, Mulder AH, Schoffelmeer ANM (1993) Chronic activation of mu and kappa-opioid receptors in cultured catecholaminergic neurons from rat brain causes neuronal supersensitivity without receptor desensitization. J Pharmacol Exp Ther 268 595-9 Schlicker E, Kathmann M (2001) Modulation of transmitter release via presynaptic cannabinoid receptors. Trends Pharmacol Sci 22 565-572... 

Tlie function of G protein-coupled receptors, such as the opioid and cannabinoid receptors, can be regulated by the process of heterologous desensitization. Wliich of the following statements is tnxe about tliis regulatory mechanism ... 

Chronic exposure to /I -THC and other cannabinoid receptor agonists generally leads to biological adaptive mechanisms that may be related to the phenomenon of tolerance. Cellular modifications in response to chronic agonist stimulation have included cannabinoid receptor down-regulation, as well as desensitization of signal transduction pathways. These effects have been recently reviewed in detail (Sim-Selley 2003). 

Phosphorylation ofthe Cannabinoid Receptors as a Mechanism for Desensitization... 

Jin W, Brown S, Roche JP, Hsieh C, Celver JP, Kovoor A, Chavkin C, Mackie K (1999) Distinct domains of the CBI cannabinoid receptor mediate desensitization and internalization. J Neurosci 19 3773-3780... 

Both in vivo and in vitro, different cannabinoid compounds can produce various degrees of tolerance and desensitization, suggesting their actions at cannabinoid receptors may not be identical (Dill and Howlett 1988 Fan et al. 1994). In a comparison of three cannabinoid agonists, the most potent compound (CP 55,940)... 

The normal internalization of the wild-type receptor, defined as a loss of cell surface receptors (measured by decreased maximal binding or B ), was unaffected for the desensitization-deficient Thr mutant (see Fig. 6.4C,D) but may have been affected when distal carboxyl terminal residues were mutated (see Fig. 6.3). Therefore some, although not all, GPCRs show radical dissociation between desensitization and internalization. This is found not only in the dopamine Dj receptor (122) but also in the N-formyl peptide (134), the CBl cannabinoid (17), and the M2 muscarinic (155) receptors. 

Keywords Adenylyl cyclase Aminoalkylindole Anandamide Ca Cannabinoid Cyclic AMP Depolarization suppression of inhibition or excitation Desensitization Endocannabinoid G proteins Ion channels Mitogen activated protein kinases Neurotransmission Nitric oxide Serine/threonine kinases Seven-transmembrane spanning receptors Synaptic plasticity Tyrosine kinases... 

Cannabinoids, endocannabinoids, alcohol, and other abused substances of interest are either co-applied or preapplied for a measured period of time such as 30-60 s with a period of about 5 min between applications to allow for drug washout and receptor recovery from desensitization. A schematic illustration of the expression system and electrophysiological recording is presented in Fig. 6. 

After establishing whether the tissues are responding to the ai-adrenoceptor or P2X receptor agonist (see Subheading 3.4.), either a cannabinoid or its vehicle is added to the organ bath, after which (time interval Y) a cumulative concentration-response curve is constructed for the chosen ai-adrenoceptor or P2X receptor agonist. This is achieved by adding the next dose to the bath as soon as the contractile response to the previous dose is complete, a protocol that reduces the risk of desensitization and that results in a dose cycle of about 2 min and in the production of a complete concentration-response curve within about 10 min (see also Fig. 3). To avoid desensitization problems, it is advisable not to attempt to obtain more than one concentration-response curve from any one tissue. 

---