The three largest classes of cell surface receptors

-rapid synaptic signaling between electrically excitable cells

-mediated by neurotransmitters

2.   G-protein-coupled receptors

-indirectly regulate the activity of membrane-bound target proteins

-mediated by a trimeric GTP-binding protein (trimeric G-protein)

3.   Enzyme-coupled receptors

-either function as enzymes or are linked with enzymes

-heterogeneous class

-most are protein kinases (or associated with protein kinases)

Structure of the GPCRs

-seven short hydrophobic stretches form transmembrane alpha helices

Trimeric G proteins relay the signals from GPCRs to other intracellular signaling proteins 

-3 subunits; alpha, beta and gamma

-Attached to the plasma membrane

-The G alpha binds a guanyl nucleotide

-Various types, each specific for a set of GPCRs and for a particular downstream target, but they all operate the same way

The trimeric G- proteins act as molecular
switches

-Inactive; Ga  bound to GDP. trimer of a, b, and g.

G-bg or confirmation change, but subunits stay together

Gs: A G-protein which acts to stimulate a target enzyme (G stimulatory )

Gi: acts to inhibit a target enzyme (G inhibitory)

Ligand binding to GCPR and cAMP regulation

-ligand binding to a GPCR can lead to a rise in intracellular cAMP via regulation of adenylyl cyclase

-•Binding site for adenylyl cyclase is

Unmasked

Terminating the Response

-carboxy terminal tail of the receptor becomes phosphorylated

-phosphorylated tail is bound by proteins (arrestins) which

sterically block receptor/G-protein interaction.

-enhanced by target enzyme

-enhanced by RGS proteins

(regulator of G-protein signaling)

cAMP exerts its effects mainly by.......

-cAMP exerts its effects mainly by activating cyclic-AMP-dependent protein kinase (PKA)

Two types; cytosol or anchored to membranes

PKA targets can be cytoplasmic or nuclear

in metabolic pathways

alter gene expression

(cAMP response element binding protein)

-   PKA catalytic subunits move into

  the nucleus

  transferases (HAT)

-  transcription is initiated 

The life and death of cAMP;
terminating the signal

-The only means of degrading cAMP

Non-selective inhibitors: Xanthines

  caffeine and theophylline

b-blockers: b1 antagonists

b1 receptors found in cardiac muscle, promote increased heart rate

- b1 antagonists slow heart rate and are b1 selective

-treat ailments associated with stress; high blood pressure, angina, irregular heart rhythms, migraines

-prevention of second heart attacks

-acebutolol, atenolol, metoprolol (lopressor)

Chronic PTH vs Intermittent PTH

Chronic leads to bone resorption

Intermittent leads to bone formation

Alterations to the parathyroid hormone receptor in human disease

-short-limbed dwarfism

-severe growth plate abnormalities, increased bone

resorption with normal/low levels of PTH

-two point mutations identified

-constitutive activity of the PTHR (agonist-independent)

-mutations alter receptor conformation to “on”