Agonist-specific coupling

 Agonist-specific coupling

On the other hand, receptors may be promiscuous as well and couple to more than one G protein. Many receptors appear to be pre-associated with G proteins in the absence of agonists. The pre-bound G protein may in turn change the conformation of the entire receptor and thus modify its affinity for mediator and drug molecules. If there is more than one type of G protein to couple to a given receptor, this may result in several sub-populations of the receptor that may exhibit diverging affinities for different agonists. This behaviour is known as `agonist-specific coupling'.

 

An example of agonist-specific coupling is shown in Fig-ure 8.3. The receptor in question is the α1A-adrenergic re-ceptor. This receptor triggers at least two different intracel-lular signaling pathways: Arachidonic acid is released by phospholipase A2, and inositoltriphosphate (IP3) is released by phospholipase C. These two effects are mediated by two different G proteins that couple to the same receptor. If we compare the two parameters, the three compounds nore-pinephrine and meta- and para-octopamine yield substan-tially different potencies and efficacies. If we hadn't been told otherwise, we would interpret this observation as evi-dence of two different receptors. In a sense, of course, dif-ferent GPCR-G protein complexes are different receptors.


Comments

Post a Comment

Popular posts from this blog

Drugs and drug target molecules

Image
  Drugs and drug target molecules   Drugs need to bind to target molecules. Is there anything remarkable about this statement at all? Well, two things:   1.    It is a surprisingly recent insight – only about 100 years old. (OK, so that is relative – long ago for you, but I'm nearly there.)   2.    It is not generally true.   The idea of defined receptor molecules for drugs or poisons was conceived by Paul Ehrlich (Figure 1.4). Ehrlich worked on a variety of microbes and microbial toxins. He observed  that many dyes used to stain specific structures in micro-bial cells in microscopic examinations also exerted toxic effects on the microbes. This observation inspired him to systematically try every new dye he could get hold of (and new dyes were a big thing in the late 19 th  century!) on his microbes. Although not trained as a chemist himself, he managed to synthesize the first effective antibacterial drug – an organic mercury compou...
Read more

Drug molecules may or may not have physiological counterparts

Image
  Drug molecules may or may not have physiological counterparts   The vasoconstricting action of angiotensin can also be countered at the membrane receptor directly. One such inhibitor that has been around for quite a while is saralasin (Figure 1.6c).   Saralasin illustrates that the structure of the physiological mediator or substrate is a logical starting point for the syn-thesis of inhibitors. However, it is not a completely satisfac-tory drug, because it cannot be orally applied – can you see why? The more recently developed drug valsartan (Figure 1.6d) is orally applicable, but has very limited similarity to the physiological agonist.   Enalapril and valsartan represent the two practically most important functional groups of drugs, respectively – en-zyme inhibitors, and hormone or neurotransmitter receptor blockers. Another important group of drugs that act on hormone and neutotransmittor receptors are `mimetic' or agonistic drugs. However, there is no clinicall...
Read more

Ion gradients across the cell plasma membrane

Image
  Ion gradients across the cell plasma membrane All membrane potentials depend on the existence of ion gradients across the membrane in question. The major ion species that shape the form of both resting potentials and action potentials are K + , Na + , Ca ++ , and Cl - . The ion gradi-ents result from the activities of three types of membrane proteins:   1.Ion pumps. These proteins use metabolic energy in the form of ATP to transport ions against their concentra tion gradients. Quantitatively the most important ion pump is Na + /K + -ATP'-ase (Figure 4.1), which transports both sodium and potassium against their respective gra-dients (table 4.1). In addition, various types of calcium pumps are found in the cytoplasmic, ER and mitochon-drial membranes; the direction of Ca ++  transport is al-ways from the cytosol to the other compartment.   2.    Exchange- and co-transporters. These link the gradients of different ion species to one another, so that gradien...
Read more