Medical Pharmacology Chapter 5:  Autonomic Pharmacology:  Adrenergic Drugs

• Adrenergic agonist-receptor interaction and activation of signaling pathway

  • Overview of drug-receptor interaction categories: 

    • Most drugs or in general "ligands" interact with receptors with the consequence of either activating a receptor with subsequent biological effects or blocking the receptor.

      • The former category of interactions refers to agonist interactions; whereas, blockers are antagonists.

        • (1) Some intracellular receptors act at the DNA or gene level, changing gene expression by interacting with "response elements" or specific target DNA sequences.²¹

          • Examples of substances which work in this way include steroids (mineralocorticoids, corticosteroids, vitamin D, and sex steroids), and thyroid hormones.

          • Hormonal actions mediated by changes in gene expression tend to occur after some delay, reflecting time to synthesize new proteins or, more generally, transition to a new steady-state level of gene product.²¹

          • Once the new steady-state has been established, transition back to the original condition may also require some extended time. 

          • The extended time might be required for transiently elevated protein concentration, as an example, to return to lower levels.

        • (2) Another receptor class involves ligand interaction with a membrane-integrated enzyme, for example receptor tyrosine kinases.²¹

          • In this setup, the ligand interacts with an extracellular domain, the consequence of which is a change in intracellular, cytoplasmic enzyme activity.

          • One important class of enzymes in this group is the tyrosine kinases, which catalyze phosphorylation reactions.

             

            • Inactive Form of Tyrosine Kinase²²

              Inactive Form of Tyrosine Kinase, prior to binding of an activating ligand.22

            •  

              Active Form of Tyrosine Kinase²²

              Active Form of Tyrosine Kinase:  Notice that binding of the "signal molecules" favors monomeric association, phosphorylation of the enzyme tyrosine residues and phosphoryl group transfer to now associated proteins. Cellular responses then ensue.22

            • Another kinase class in which the amino acid serine is central in phosphoryl-group transfer is the serine kinases.

            • Lastly,  guanylyl cyclases represent another important enzyme class.

               

      • (3)  Cytokine receptors represent another class.²¹

        • Ligands which are peptides bind to these receptors.

        • Upon activation by the peptides, the dimeric receptor form is favored (association of two receptor monomers) and a previously associated tyrosine kinase transitions to the catalytically active form.

        • The subsequent step involves phosphorylation by this activated tyrosine kinase of other molecules, STATs which is an abbreviation for Signal Transducers and Activators of Transcription in the cell nucleus).

          • The tyrosine kinase involved in the system is described as a Janus kinase (JAK).

      • Cytokine Signal Transduction Pathway:  STAT Activation²³

        As shown above, several pathways can lead to STAT activation. Highlighted is the pathway mediated by cytokines via the cytokine receptor and JAK (Janus kinase, a tyrosine kinase). 23 Following STAT phosphorylation by JAK, the phosphorylated STAT monomers bind to a special structural region, the SH2 domain, located on another STAT monomer. The SH2 domain references "Src-homology 2" which is described as a common structural feature among signaling molecules which promote protein-protein association through direct phosphotyrosine interaction. SH2 domain: beta sheet (green) + two alpha-helices (orange & blue)24 This is the structurally conserved protein domain of the Src oncoprotein.25 This domain is found in many signal-transducing proteins25. Src (sarcoma) is a group of proto-oncogenic tyrosine kinases. STAT dimers translocate to the nucleus where binding to specific DNA-response elements results in target gene promoter activation and gene expression initiated.23

    • (4) Ligand-Gated and Voltage-Gated Channels:^21,27

      • Many drugs and even toxins act by either producing effects similar to endogenous ligands or by blocking such effects at the level of ion channels.

        • Some receptor systems act by regulating the extent to which certain ions move across biological membrane.

        • These receptors alter the tendency of ion movement i.e. change membrane conductance with respect to certain ion(s).

        • Endogenous agents which represent substances naturally occurring within the body that act by modulation of ion conductance through ligand-gated channels include acetylcholine, GABA, glutamate, and serotonin (5-HT).

         

      • An example of a ligand-gated channel is the nicotinic cholinergic receptor, which consists of several subunits.

        • Illustration of an Acetylcholine Receptor (Illustration: Giovanni Maki)²⁸

          The nicotinic cholinergic (ACh) receptor consists of five subunits (two α, one β, one γ and one δ).27 Binding of acetylcholine to an α-subunit binding domain induces a change in receptor geometry enabling increased ion flow down the central core 27 (see representation below).

        • Ion flow through a central core, as describe below:

          • 3D Representation of the Nicotinic Acetylcholine Receptor^29,30

          • These images were developed utilizing cryoelectron microscopy (9 Å resolution). One view shows the receptor from the side (left image) where is the second view is from above (right image). The subunits are described as exhibiting 5-fold symmetry around the central pore as suggested by the image on the right.29,30

      • Voltage-gated channels alter ion conductance in accord with the membrane potential, without requiring activation by neurotransmitters; however, some drugs act by affecting channel responses to membrane potential changes.²⁷

        • One example is the Ca²⁺ channel inhibitor verapamil.

          • Verapamil (Ca²⁺ channel inhibitor)

          • Blockade of myocardial Ca²⁺ channels can alter conduction velocity and cardiac contractility (a negative inotropic effect). Vascular effects of Ca²⁺ channel inhibition include blood pressure reduction.²⁷