Agonist-bound state

GPCRs in order to serve as templates and aid in the analysis of ligand-receptor complexes. Thus, the validated structural insights described earlier show that it is not appropriate to utilize the crystal structure of the inactive form of rhodopsin as a universal template if the modeled functional details pertain to an activated (e.g., agonist-bound) state of the GPCR. 

Two-state theory was originally formulated for ion channels. The earliest form, proposed by Del Castillo and Katz [15], was comprised of a channel that when bound to an agonist changed from a closed to an open state. In the absence of agonist, all of the channels are closed ... 

While the extended ternary complex model accounts for the presence of constitutive receptor activity in the absence of ligands, it is thermodynamically incomplete from the standpoint of the interaction of receptor and G-protein species. Specifically, it must be possible from a thermodynamic point of view for the inactive state receptor (ligand bound and unbound) to interact with G-proteins. The cubic ternary complex model accommodates this possibility [23-25]. From a practical point of view, it allows for the potential of receptors (whether unbound or bound by inverse agonists) to sequester G-proteins into a nonsignaling state. 

There are some specific differences between the cubic and extended ternary complex models in terms of predictions of system and drug behavior. The first is that the receptor, either ligand bound or not bound, can form a complex with the G-protein and that this complex need not signal (i.e., [ARiG] and [RjG]). Under these circumstances an inverse agonist (one that stabilizes the inactive state of the receptor) theoretically can form inactive ternary complexes and thus sequester G-proteins away from signaling pathways. There is evidence that this can occur with cannabi-noid receptor [26]. The cubic ternary complex model also... 

Agonists activate nAChR by binding to the agonistbinding site (Fig. 1). They can remain bound (often with higher affinity) when the nAChR enters the desensitised state. 

The sequences of events that occur during activation of adenylate cyclase after receptor occupancy are shown in Figure 6.3. This scheme thus shows activation of a Gofc-type protein (i.e. a process that leads to the activation of adenylate cyclase), whereas similar processes will occur with a Ga protein, except that the interaction with adenylate cyclase will result in its inactivation. In the same way, activation of phospholipases by mobile Ga-type subunits will occur via similar mechanisms. In the unstimulated state, Gas (or Gcq) is bound to GDP. Binding of the receptor with its agonist induces a conformational change in the receptor that activates its G-protein. This stim-... 

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