Материал: 2016_Kaplan_USMLE_Step_1_Lecture_Notes_Pharmacology

In A Nutshell

Key ANS Receptors

M1, M3, α1:

Gq activation of phospholipase C

M2, α2, D2:

Gi inhibition of adenylyl cyclase

β1, β2, D1:

Gs activation of adenylyl cyclase

Receptors Linked Via Coupling Proteins to Intracellular Effectors

λMany receptor systems are coupled via GTP-binding proteins (G-proteins) to adenylyl cyclase, the enzyme that converts ATP to cAMP, a second messenger that promotes protein phosphorylation by activating protein kinase A. These receptors are typically “serpentine,” with seven transmembrane spanning domains, the third of which is coupled to the G-protein effector mechanism.

λProtein kinase A serves to phosphorylate a set of tissue-specific substrate enzymes or transcription factors (CREB), thereby affecting their activity.

GS PROTEINS

λBinding of agonists to receptors linked to Gs proteins increases cAMP production.

λSuch receptors include those for catecholamines (beta), dopamine (D1), glucagon, histamine (H2), prostacyclin, and some serotonin subtypes.

GI PROTEINS

λBinding of agonists to receptors linked to Gi proteins decreases cAMP production.

λSuch receptors include adrenoreceptors (alpha2), ACh (M2), dopamine (D2 subtypes), and several opioid and serotonin subtypes.

GQ PROTEINS

λOther receptor systems are coupled via GTP-binding proteins (Gq), which activate phospholipase C. Activation of this enzyme releases the

second messengers inositol triphosphate (IP3) and diacylglycerol (DAG) from the membrane phospholipid phosphatidylinositol bisphosphate

(PIP2). The IP3 induces release of Ca2+ from the sarcoplasmic reticulum (SR), which, together with DAG, activates protein kinase C. The protein kinase C serves then to phosphorylate a set of tissue-specific substrate enzymes, usually not phosphorylated by protein kinase A, and thereby affects their activity.

λThese signaling mechanisms are invoked following activation of recep-

tors for ACh (M1 and M3), norepinephrine (alpha1), angiotensin II, and several serotonin subtypes.

Cyclic GMP and Nitric Oxide Signaling

λcGMP is a second messenger in vascular smooth muscle that facilitates dephosphorylation of myosin light chains, preventing their interaction with actin and thus causing vasodilation.

λNitric oxide (NO) is synthesized in endothelial cells and diffuses into smooth muscle.

λNO activates guanylyl cyclase, thus increasing cGMP in smooth muscle.

λVasodilators ↑ synthesis of NO by endothelial cells.

Receptors That Function as Enzymes or Transporters

λThere are multiple examples of drug action that depend on enzyme inhibition, including inhibitors of acetylcholinesterase, angiotensinconverting enzyme, aspartate protease, carbonic anhydrase, cyclooxygenases, dihydrofolate reductase, DNA/RNA polymerases, monoamine oxidases, Na/K-ATPase, neuraminidase, and reverse transcriptase.

λExamples of drug action on transporter systems include the inhibitors of reuptake of several neurotransmitters, including dopamine, GABA, norepinephrine, and serotonin.

Bridge to Biochemistry

See Chapter 9 of the Biochemistry Lecture Notes for additional discussion of signal transduction.

Clinical Correlate

Drugs acting via NO include nitrates (e.g., nitroglycerin) and M-receptor agonists (e.g., bethanechol).

Endogenous compounds acting via NO include bradykinin and histamine.

Clinical Correlate

Imatinib is a specific tyrosine-kinase (TK) inhibitor, while sorafenib is a non-specific TK inhibitor.

Receptors That Function as Transmembrane Enzymes

λThese receptors mediate the first steps in signaling by insulin and growth factors, including epidermal growth factor (EGF) and platelet-derived growth factor (PDGF). They are membrane-spanning macromolecules with recognition sites for the binding of insulin and growth factors located externally and a cytoplasmic domain that usually functions as a tyrosine kinase. Binding of the ligand causes conformational changes (e.g., dimerization) so that the tyrosine kinase domains become activated, ultimately leading to phosphorylation of tissue-specific substrate proteins.

λGuanyl cyclase−associated receptors: stimulation of receptors to atrial natriuretic peptide activates the guanyl cyclase and ↑ cyclic GMP (cGMP)

Receptors for Cytokines

λThese include the receptors for erythropoietin, somatotropin, and interferons.

λTheir receptors are membrane spanning and on activation can activate a distinctive set of cytoplasmic tyrosine kinases (Janus kinases [JAKs]).

λJAKs phosphorylate signal transducers and activators of transcription (STAT) molecules.

λSTATs dimerize and then dissociate, cross the nuclear membrane, and modulate gene transcription.