Receptors and Cell Signaling

definition: short distance signaling.

example: Cytokines and NMJ

paracrine signaling

definition: short distance with same type of cell or the same cell

example: Prostaglandins (inflammatory molecules)

autocrine signaling

definition: long distance signaling, typically with a long half life, slow cell response, and travel while bound to carriers

example: hormones

endocrine signaling

The chemical signal

How the cells detect the chemical signal

The major mechanisms that respond to the ligand

Regulation of cell response

general steps of signaling

Ligand: ACH

Receptors:

Nicotinic ACh receptors (muscle)

Muscarinic ACh receptor (heart muscle)

Response:

ion channels for NACHr (Na+ inside and K+ outside, anti-porter that is powered by Na/K electrochemical gradient) --> stimulate muscle contraction

G protein-linked receptor for MACHr (moved K+ out of the cell) --> decreased heart contraction

Regulation: Ach esterase

general steps of signaling of the NMJ

Treats MG

Binds with Type I and Type II hormone receptors to suppress NACHr autoantibodies.

prednisone

treats organophosphates poisoning

an muscarinic ACh receptor antagonist

atropine

SarinVX (nerve gas) and insecticides

causes irreversible inhibition of ACh esterase, causes an increase in Ach signaling

organophosphates

Derived from AAs and their derivatives (glycine, glutamate, dopamine, acetylcholine)

Examples: neuropeptides (endorphin, enkephalin, etc)

One of the 5 major groups of chemical signalers

Neurotransmitters

Derived from amino acid derivatives and steroids

Examples: epinephrine

(testosterone, progesterone, cortisol, etc) [hydrophobic]

vitamin D3, retinoic acid - vitamin-derived (not endocrine)[hydrophobic]

One of the 5 major groups of chemical signalers

hormones

Derived from proteins

Examples: (interferons, interleukins etc)

One of the 5 major groups of chemical signalers

Cytokines

Derived from arachidonic acid

Examples: (prostaglandins, leukotrienes, thromboxanes)

One of the 5 major groups of chemical signalers

Eicosanoids

Derived from proteins, controls cell differentiation and proliferation

Examples: (epithelial growth factor, platelet-derived growth factor, etc)

One of the 5 major groups of chemical signalers

Growth factors

Where: cytosol

Binds to:

[TYPE 1] P-CAT (progesterone, cortisol, aldosterone, testosterone)

[TYPE 3] estradiol

Functions by: shedding HSP (heat shock protein) and dimerizing (makes a NR dimer) to move into the nucleus (via nuclear pore). Binds to DNA with help of cofactors and acts as a TF (transcription factor)

Type I/III receptors

anti-inflammatory steroid drug that binds to Type I/III receptors

Dexamethasone

Where: nucleus

Binds to: (Retinoic Acid, Vitamin D3, Thyroid Hormone, Fatty Acids)

Functions by: binds to ligand, forming a heterodimer that binds to DNA. Removal of a corepressor by a coactivator activates the dimer, which then acts as a TF

Type II receptor

binds to a FA receptor (PPARy) to increase insulin sensitivity (treats DM II)

TZD/Thiazolidinediones

Binds to: NO (nitrogen oxide)

Functions by: releasing cGMP upon ligand/receptor binding; causes vasodilation in smooth muscle

guanylate cyclase

drugs that decompose to nitric oxide, and so causes guanydyl cylase to react

nitroglycerin, nitroprusside, hydroxyurea

Where: cell membrane

Binds to: Ach and other molecules

Functions by: ligand and receptor binding changes the movement of ions across the membrane, mainly used in the CNS and PNS (convert a chemical signal to an electrical signal)

Ion Channel-Linked Receptors

Where: cell membrane

Binds to: insulin

Uses: MAPK, PLC γ, and PI 3-kinase pathway
Functions by:
1. Dimerization of receptor
2. Making of RAS protein receptor complex
3. RAS exchanges GDP for GTP, and then acts as a TF when activated

Enzyme/Enzyme-Linked Receptors

Where: cell membrane

Binds to: adenosine

Causes: decreased HR

Adenosine1 receptor

Where: cell membrane

Binds to: adenosine

Causes:

Coronary artery vasodilation

Decreased dopaminergic activity in CNS

Inhibition of central neuron excitation

Adenosine2a receptor

Where: cell membrane

Binds to: adenosine

Causes:

Cardiac muscle relaxation

Cardioprotection in cardiac ischemia

Adenosine3 receptor

Adenosine antagonist

causes increased HR and releives tension related headaches

caffeine

Where: cell membrane

Binds to:

epinephrine, norepinephrine (adrenergic)

glucagon

Ach

rodopsin

dopamine

Functions by: ligand/receptor bindings activates the 7 transmembrane domain bound to the __-protein, causing a signal cascade with 2nd messengers

G-Protein-Linked Receptors

Type of G-Protein-Linked Receptor

causes: metabolic effect of glucagon during fasting.

pathway type: protein kinase A (PKA)

Glucagon receptor

Type of G-Protein-Linked Receptor (α1, α2, β1, β2, β3)

causes: regulation of heart-rate, smooth muscle constriction, metabolism

pathway type: protein kinase A (PKA) or protein kinase C (PKC)

Adrenergic (epinephrine, norepinephrine) receptors

Targets: ____ adrenergic receptors (a GCPR)

causes: prevention of cardiac arrhythmias by blocking signal to stimulate heart rate

B1 blockers

Type of G-Protein-Linked Receptor

responds to: light

Gasubtype: Gat

pathway: phosphodiesterase --> cGMP

causes:

1. a photon activates rhodopsin

2. rhodopsin activates transducin

3. transducin activates phosphodiesterase

4. phosphodiesterase hydrolyses cGMP

5. the decrease in cGMP causes the close of closes cGMP-

gated ion channels

rhodopsin receptor

Type of G-Protein-Linked Receptor

Targeted by medication in order to treat-

schizophrenia,

Parkinson's disease

attention deficit disorders

dopemine receptor

special enzymes that ADD phosphate groups to proteins WITH ATP

form of post-translational modification

ex: glukagon

kinases

remove phosphate groups via H2O

ex: insulin

phosphatase

Type of intracellular GCPR cascade

Uses: protein kinase A

Functions by:

1. receptor/ligand binding causes Gsa facilitated activation of ADENYLATE CYCLASE

2. Andenylate cyclase makes cAMP to activate PKA

3. PKA activates phosphorylase kinase and

deactivates glycogen synthase

4. glycogen is degraded (glycogenolysis)

PKA GCPR pathway

cAMP binds to _____, causing dissociation of regulatory subunits

and activation of catalytic subunits

PKA activation

Ga subtype: Gi

pathway: decrease cAMP--> PKA

α2- adrenergic receptors

alpha subunit of the G protein that stimulates adenylate cyclase and increases cAMP release

ligands: glucagon, epinephrine, ACTH

Gsa

Ga subtype: Gs

pathway: increase cAMP--> PKA

causes: increase HR

B1 adrenergic receptors

Ga subtype: Gs

pathway: increase cAMP--> PKA

causes: glycogenolysis and glycogen metabolism (glycogenolysis)

B2 adrenergic receptors

Acts on: GsaCPR

Causes:

ADP-ribosylation of Gsa

Which keeps GTP from being used up --> constant activation of the Gsa subunit

Leads to constant activation of adenylate cyclase

Causes increased cAMP and PKA levels

Cholera toxin

alpha subunit of the G protein that inhibits adenylate cyclase decreases cAMP release

ligands: PGE1 and adenosine

Gia

Acts on: GiaCPR

Causes:

ADP-ribosylation of Gia

Which keeps GDP from being exchanged --> constant deactivation of the Gia subunit

Leads to no inhibition of adenylate cyclase

Causes increased cAMP and PKA levels

Pertussis Toxin

Type of intracellular GCPR cascade

Used by: α1-adrenergic receptors

Functions by:

1. Gq subunit activating ____

2. ____ then activates DAG, and IP3

3. IP3 cause the release of Ca2+ from the smooth ER

4. CA2+ and DAG stimulates PKC

phospholipase CB GCPR pathway

Ga subtype: Gq

pathway: Ca2+, DAG, and IP3 --> PKC

causes: Vasoconstriction and Dilation of pupils

α1-adrenergic receptor

used in decongestants and eye drops

reacts with Gq subunit and PKC pathway

α1-adrenergic agonists

Type of intracellular GCPR cascade

Used by: Muscarinic ACh Receptor

Uses: βγ subunits of G protein

Functions by: βγ subunits opens ion channel

ion channel modulation GCPR pathway

Type of Enzyme or Enzyme-Linked Receptors

Used by: cytokines

Functions by:

1. receptor and ligand binding causes receptor dimerizing and JAK binding to receptor

2. JAKs phosphorylate each other and receptor

3. STATs bind and are phosphorylated by the receptor

4. Phosphorylated STAT translocates to the nucleus and acts as a TF

JAK-STAT Receptors

Type of Enzyme or Enzyme-Linked Receptors

Used by: transforming growth factor β family.

Functions by:

1. Ligand receptor binding causes phosphorylation of the receptor

2. The phosphorylated receptor phosphorylates R-SMAD

3. activated R-SMAD acts as a TF

Serine-Threonine Kinase Receptors

Type of Enzyme or Enzyme-Linked Receptors

Used by: many growth factors (insulin)

ACTIVATES: MAPK, PLC γ, and PI 3-kinase pathway

Functions by:

1. Dimerization of receptor

2. Making of RAS protein receptor complex

3. RAS exchanges GDP for GTP, and then acts as a TF when activated

Tyrosine Kinase Receptors

regulates transcription & translation

of genes necessary for glucose metabolism

insulin MAPK

Causes GLUT4 to be moved to the cell membrane for increased glucose uptake by muscle and adipose tissue

insulin PI-3K

Activates lipid/glycogen synthesis for excess glucose storage

insulin PLCγ