Biochemistry Online: An Approach Based on Chemical Logic

Biochemistry Online





Learning Goals/Objectives for Chapter 9C:
After class and this reading, students will be able to

  • define kinases and phosphatases and their role in signal transduction
  • define primary and secondary messengers and give specific examples of each
  • describe the role of G proteins in coupling ligand induced conformational changes in the bound receptor to activation of specific effector proteins such as adenylate cyclase and phospholipase
  • differentiate between kinases activated by second messengers and those activated by primary messengers (ligand-gated receptor Tyr kinases)
  • describe the structural characteristics of G protein coupled serpentine receptors and ligand gated receptor tyrosine kinases
  • draw a diagram showing the general features of kinases mediated signal transduction pathways that lead to activation of gene expression
  • differentiate between neuron responses mediated by neurotransmitters on binding gated receptor/ion channels compares to G-protein coupled receptors

Estonian Translation by Anna Galovich

C2. Protein Kinase A (PKA)

Cascade of events:  A transmembrane receptor  WITHOUT ENZYMATIC ACTIVITY binds an extracellular chemical signal, causing a conformational change in the receptor which propagates through the membrane.  The intracellular domain of the receptor is bound to an intracellular heterotrimeric G protein (since it binds GDP/GTP) in the cell.  The G protein dissociates and one subunit interacts with and activates an enzyme - adenylate cyclase- which converts ATP into a second messenger - cyclic AMP (cAMP) - in the cell. cAMP activates protein kinase A (PKA) which phosphorylates proteins at specific Ser or Thr side chains. 

Figure: cyclic AMP

Receptors which work through an intermediary G protein usually are single polypeptide chains that span the membrane seven times in a serpentine fashion.


Updated Gs-alpha/adenylate cyclase complex   Jmol14 (Java) |  JSMol  (HTML5) 

Some signals that activate adenylate cyclase and use cAMP as a second messenger include:  corticotrophn, dopamine, epinephrine (β-adrenergic), follicle-stimulating hormone, glucagon, many odorants, prostaglandins E1and E2, and many tastants.


Some enzymes regulated by cAMP-dependent phosphorylation by PKA

Enzyme Pathway
Glycogen Synthase glycogen synthesis
Phosphorylase Kinase glycogen breakdown
Pyruvate Kinase Glycolysis
Pyruvate Dehydrogensae Pyruvate to acetyl-CoA
Hormone-sensitive Lipase Triacylglyeride breakdown
Tyrosine Hydroxylase Synthesis of DOPA, dopamine, norepinephrine
Histone H1 Nucleosome formation with DNA
Histone H2B Nucleosome formation with DNA
Protein phosphatase 1 Inhibitor 1 Regulation of protein dephosphorylation
CREB cAMP regulation of gene expression
PKA cosensus sequence XR(R/K)X(S/T)B  (B = hydrophobic amino acid)

An example of how epinephrine (a flight/fight hormone) can lead to breakdown of glycogen (your main carbohydrate reserves in muscle and liver) is shown below.  A cascade of events, starting with the binding of the hormone to its receptor, followed by activation of adenylate cyclase, which forms cAMP, which activates PKA, which leads to the activation of the enzyme that breaks down glycogen (glycogen phosphorylase) is shown. (For simplicity, G protein involvement is not shown.)

Figure:  Activation of glycogen phosphorylase through activation of PKA.

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