CB1/D2 heterodimers coupled positively to cAMP/Gs develop with CB1/D2 agonism?

[Cotcha Yankinov]

http://molpharm.aspetjournals.org/content/67/5/1697.long - Concurrent Stimulation of Cannabinoid CB1 and Dopamine D2 Receptors Enhances Heterodimer Formation - "The consequence of this interaction is a differential preference for signaling through a “nonpreferred” G protein. In this case, D2 receptor activation, simultaneously with CB1 receptor stimulation, results in the receptor complex coupling to Gαs protein in preference to the expected Gαi/o proteins. The result of this interaction is an increase in the second messenger cAMP"

http://www.ncbi.nlm.nih.gov/pubmed/27089415 - " Combined CB1 plus D2 agonists in MN9D cells converted the CB1 agonist-mediated activation of Gi to inhibition of Gi. In these models, the CB1 agonist response was converted to an inverse agonist response at Gi activation. Cannabinoid agonist-stimulated cAMP accumulation can be best explained as reduced activation of Gi, thereby attenuating the tonic inhibitory influence of Gi on the major isoforms of adenylyl cyclase."

First off, are we to assume that the same heterodimers can form with THC/endogenous dopamine?

Second, if under conditions of excess dopamine (amphetamines etc.) and CB1 agonism these excitatory coupled CB1/D2 heterodimers can form, couldn't they be playing a big role in abuser's issues? It seems like CB1/D2 receptors coupled to excitatory pathways located on glutamate etc. could be of consequence, and then you might also experience kindling/downstream compensation from CB1/D2 coupled to Gs located on MSNs.

 

[theGirlWithBlueHair]

lol did you steal my information?

 

[Cotcha Yankinov]

Hehehehe maybe :D The other thing I'm curious about is the whole high affinity state D2 receptor that can form with schizophrenia/after amphetamines thing - wouldn't it be something if you could form these CB1/D2 receptor complexes with the high affinity D2?

It makes me wonder though, the mu opoid receptor is known to switch from inhibitory Gi/o to excitatory Gs signaling with excess agonism, so how many other receptors can change their signaling like these examples before us?

 

[theGirlWithBlueHair]

The mu receptor is coupled to an inward rectifying GIRK channel. Which is what the GABA B receptor and D2 receptor are coupled to (they share the exact same one) and they are both known to cause hypomanic/manic behavior and delusions/hallucinations (GABA B agonists do during cessation and withdrawals - probably due to the lack of GABA B receptors and the hyperdopaminergic state that results as an excessive activation of D2 channels and opening of GIRK channels occurs).

The GIRK channels are coupled to what are called t-type calcium channels, which are low voltage gated, and which open when the membrane potential is low. They are called low threshold spikes and increase activity greatly in the thalamocortical circuit, which is why baclofen causes absence seizures. (which makes me wonder why phenibut does not, it being a GABA B agonists...its activity at the GABA A receptor must be veracious...)

This is why these ligands cause depolarization and excitation. Even though the GIRK channels are massively inhibitory. This is why D2 agonists can cause sudden sleep attacks but you can get manic off them, yet suddenly fall asleep out of nowhere too.

Or on high dosages you can get hypomanic, then suddenly nod on a drop of a dime with your head just falling for a few seconds, then be up and hypomanic again.

Or with mu agonists and their heavy nodding, yet stimulating properties. Their switching from inhibitory to stimulating - and back and forth - is from the mu opioid receptors eventually causing enough t-type calcium channel activation, and subsequent, glutamate and dopamine release, along with norepinephrine, in the subsequent synaptic space, while also causing inhibition as well.