My Twitter Mini Review of Pharmacology

Perhaps I need to write the story of how receptors work on Twitter? Humm, which hashtag(s) to use? - #receptor #pharmacology #science

Work at the turn of the last century summarized at - http://ow.ly/R8Hl led to the lock & key concept #receptor #pharmacology #science

Here's a modern version of the "lock and key concept" for the receptor response - http://ow.ly/R8KN #receptor #pharmacology #science

One problem is how does the binding of a small molecule alter the conformation of a much larger one? #receptor #pharmacology #science

Another problem is how do some binding molecules produce a partial or no response? #receptor #pharmacology #science

These problems & desensitization, fade or tachyphylaxis led to the two state theory - http://ow.ly/R8VQ #receptor #pharmacology

Two state mathematics only solved for the fractional or proportional change - http://ow.ly/R91A #receptor #pharmacology #science

Experiments showing an increased response with increased receptor expression didn't fit with 2 state theory #receptor #pharmacology #science

Also no consensus on what the two states of the receptor are -just active & inactive? #receptor #pharmacology #science

I suggested an alternative math to remove these problems with 2 state theory - http://ow.ly/R9jj #receptor #pharmacology #science

The idea was that the net shift could explain a binding molecule's preference - http://ow.ly/R9qX #receptor #pharmacology #science

The "net shift" (delta RH) could fit many classical dose-response curves - http://ow.ly/R9tj #receptor #pharmacology #science

We proposed that a free thiol produced the 2 (acid-base) receptor states - http://cogprints.org/4095/ #receptor #pharmacology

This was a mechanistic hypothesis of receptor function involving sulfhydryl modulation and redox regulation #receptor #pharmacology #science

This also fit nicely with the "net shift" producing the active state of the receptor #receptor #pharmacology #science

Subsequent work seems to support our observations - http://ow.ly/R9PR #receptor #pharmacology #science

Although much more work remains, it looks promising that a free thiol may explain many receptor responses #receptor #pharmacology #science

receptor activation thiol OR sulfhydryl "two state" - http://ow.ly/R9WI #receptor #pharmacology #science

@davidperrey Never seen a review by Twitter before! @rlanzara is trying it using these hashtags - check it out: #receptor #pharmacology #science

For my very mini (and biased) review of pharmacology - http://ow.ly/Rab6 #receptor #pharmacology #science

Bio Balance - Reference Library - http://www.bio-balance.com/Ref.htm

Active and Inactive Receptor States

When we write the set of brackets around a chemical species to represent a chemical concentration, it really represents a sum of probable chemical species that are grouped together. This is especially important when we consider the potential states of large protein molecules such as cellular receptors. In pharmacologic theory, we often characterize the active or inactive states of the receptor as initial quantities such as [R] and [R*]. This is convenient for mathematically manipulating these receptor states in order to derive information about how they behave in the presence of stimulating or inhibiting molecules such as agonists or antagonists, but conveys little about the underlying molecular species connected with these active and inactive states.

Even using specific and detailed molecular dynamic simulations, the meaning behind the [R] and [R*] receptor states becomes less clear when we explicitly model these states. Since there are a vast multitude of possible conformations, it becomes increasingly difficult to separate out those conformations that belong to the active or inactive receptor states. Ironically, this has brought us full circle to consider what [R] and [R*] represent as specific molecular species. The closer we are to understanding the details of these states from crystallographic structures, the further we are from understanding the molecular species that make up the active and inactive states.

Anyone who has truly studied pharmacologic theory and molecular modeling knows that we often wind up with this essential conundrum. Some have chosen particular molecular motions or interactions such as the breaking of a salt bridge or the twist or turn of a helix to describe what they think is the active receptor state. These descriptions may contain accurate descriptions of the active receptor state, but the fact that receptors exist in a sea of thermal noise and that activating drugs or ligands bind to their target receptors with only a 3-4 kcal/mol maximum energy difference and display different active molecular conformations suggest that we need a clearer on and off molecular switch for receptor activation.

These are not impossible physical constraints to accommodate in a biophysical molecular model for receptor activation (see - http://www.bio-balance.com/JMGM_article.pdf and http://www.bio-balance.com/GPCR_Activation.pdf ), but because receptors are complex molecular structures that exist in multiple domains, the teasing apart of the essential molecular signal is very difficult from both an experimental and theoretical perspective. This is particularly true if the biophysical models fail to accommodate major experimental findings such as the redox sensitivity of receptor systems or the reduction in desensitization by combining an antagonist with an agonist. A comprehensive molecular model for receptor activation should contain these findings.

Evidence for a free thiol necessary for GPCR activation

P2Y12, a G protein-coupled receptor that plays a central role in platelet activation is the receptor targeted by the antithrombotic drug, clopidogrel. The mechanism of action of clopidogrel involved cysteine 97 within the first extracellular loop of P2Y12. This provides supporting evidence for a free thiol or sulfhydryl group necessary for GPCR activation.

See - http://www.pnas.org/content/103/29/11069.full and http://www.bio-balance.com/Ref.htm