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 Kinase:  Prior to binding of an activating ligand²²

        • 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