Drug action targets

  • G protein second messenger cascade
  • Physiological antagonists
  • Intrinsic activity of receptors
  • Receptor desensitization
  • Orthosteric and allosteric

Learn.

Recall that a muscarinic ACh receptor is a g coupled-protein receptor. These have seven proteins which go into and out of the cell and allow the ‘outside’ signals to be passed inside the cell. These then form secondary messengers which have a cascade effect to create a cellular response. For example, the activation of a muscarinic receptor results in the release of G-proteins with the target enzyme adenylyl cyclase which enzymatically results in cAMP formation.

Physiological antagonists are ligands which act to inhibit the effect of an agonist through activation of an opposing physiological response by targeting a different receptor. Note this opposing physiological pathway has to be acting on a different receptor. If an agonist creates an opposing response but acts on the same receptor – it is an inverse agonist. An example of an inverse agonist is an antihistomine.

An example of a physiological antagonist is the push and pull in the heart. Pace maker/myocyte cells in the heart contain the β1-adrenoceptors. Noradrenaline and adrenaline can bind to this resulting in the G coupled-protein receptor releasing the Gs subunit. This then activates adenylate cyclase which increases cAMP. This increases heart rate and contraction through increasing Calcium ions. This is known as the push, since it results in tachycardia.

The physiological antagonist of this is the pull. This occurs when ACh binds to the muscarinic-2 ACh which results in the G protein inhibiting adenyl cyclase which limits cAMP production thereby reducing the speed of depolarization. This results in a slowing of the heart rate.

Intrinsic activity occurs in some receptors and is when the receptor may still switch to a state resulting in a biochemical change despite no agonist/ inverse agonist being bound.

Receptor desensitization results in a reduction in the binding of the ligand to the receptor. This can occur in minutes due to there no longer being coupling, this means that the secondary messenger cascade is no longer being activated. Over hours, a reduction in the number of exposed receptors can occur. This is known as receptor translocation and can be due to endocytosis of the receptors. Overuse of a chemical pathway can reduce the mediator carrying the message, amine in the nerve terminal are often depleted from overuse of amphetamines. This is known as mediator exhaustion.

Orthosteric binding is when the ligand binds to the receptor at the active site or allosteric binding which is when the ligand binds to the surface of the protein not on the active site. This results in allosterical changes to the conformation of the protein. Thereby changing the free energy landscape of the protein.

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