Enzyme-Linked Receptors

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Chapter: Essential pharmacology : Pharmacodynamics Mechanism Of Drug Action; Receptor Pharmacology

This class of receptors have a subunit with enzymatic property or bind a JAK (Janus Kinase) enzyme on activation. The agonist binding site and the catalytic site lie respectively on the outer and inner face of the plasma membrane.


ENZYME-LINKED RECEPTORS

 

This class of receptors have a subunit with enzymatic property or bind a JAK (Janus Kinase) enzyme on activation. The agonist binding site and the catalytic site lie respectively on the outer and inner face of the plasma membrane (Fig. 4.8). These two domains are interconnected through a single transmembrane stretch of peptide chain. There are two major subgroups of such receptors.

 

a. Those that have intrinsic enzymatic activity.

 


 

b. Those that lack intrinsic enzymatic activity, but bind a JAKSTAT kinase on activation.

 

 

a.     Intrinsic Enzyme Receptors

 

The intracellular domain is either a protein kinase or guanylyl cyclase.

In most cases the protein kinase specifically phosphorylates tyrosine residues on substrate proteins (Fig. 4.8A), e.g. insulin, epidermal growth factor (EGF), nerve growth factor (NGF) receptors, but in few it is a serine or threonine protein kinase. In the monomeric state, the kinase remains inactive. Agonist binding induces dimerization of receptor molecules and activates the kinase to autophosphorylate tyrosine residues on each other, increasing their affinity for binding substrate proteins and carrying forward the cascade of tyrosine phosphorylations. Intracellular events are triggered by phosphorylation of relevant proteins, many of which carry a SH2 domain. A general feature of this class of receptors is that their dimerization also promotes receptor internalization, degradation in lysosomes and down regulation.

 

The enzyme can also be guanylyl cyclase (GC), as in the case of atrial natriuretic peptide (ANP). Agonist activation of the receptor generates cGMP in the cytosol as a second messenger which in turn activates cGMPdependent protein kinase and modulates cellular activity.

 

 

b. JAK-STAT Kinase Binding Receptors

 

These receptors differ in not having any intrinsic catalytic domain. Agonist induced dimerization alters the intracellular domain conformation to increase its affinity for a cytosolic tyrosine protein kinase JAK. On binding, JAK gets activated and phosphorylates tyrosine residues of the receptor, which now binds another free moving protein STAT (signal transducer and activator of transcription) which is also phosphorylated by JAK. Pairs of phosphorylated STAT dimerize and translocate to the nucleus to regulate gene transcription resulting in a biological response. Many cytokines, growth hormone, interferons, etc. act through this type of receptor.

 

The enzymelinked receptors transduce responses in a matter of few minutes to a few hours.

 

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