today: epinephrine nestles in predicted binding site of predicted human 1- adrenergic receptor....

Today:

Epinephrine nestles in predicted binding site of predicted human 1-adrenergic receptor. [Proc. Nat. Acad. Sci. USA, 99, 12622 (2002)].

• Battery Types• Quiz• Cell Communication

The Basics of The Basics of Extracellular Cell SignalingExtracellular Cell Signaling

Cells can Cells can signal signal

themselves themselves ((autocrineautocrine), ), nearby cells nearby cells ((paracrineparacrine) ) or distant or distant

cells cells ((hormoneshormones).).

A Specific Example…A Specific Example…

A Specific Example…A Specific Example…

Meet the Ligands…Meet the Ligands…

R + L RLDoes this need to be reversible? If so,

which direction should be favored?

Intracellular and Extracellular Receptors

Consider Follicle Stimulating Hormone (FSH), widely used as

a fertility drug.

Do you expect this hormone to have an

intracellular or extracellular

receptor? Why? Image: Wadsworth Center, New York State Department of Health

Intracellular and Extracellular Receptors

Surface and ribbon representation showing the crystal structure of human FSH bound to the extracellular hormone-binding domain of its receptor (FSHR-HB). FSH alpha- and beta-subunits are in green and cyan, respectively. FSHR-HB is in red. A seven-helix transmembrane domain (gray, modeled on the structure of rhodopsin) anchors the receptor in the membrane. Upon receptor binding, FSH undergoes a concerted conformational change that affects the protruding loops, which may in turn play a direct role in activation through the receptor transmembrane domain. (Image: Courtesy Qing Fan

and Wayne A. Hendrickson) 2005

General RuleGeneral Rule

1. Ion Channel Receptors1. Ion Channel Receptors

Ion Channel Receptors: Remembering Ion Channel Receptors: Remembering the Sodium Potassium Pumpthe Sodium Potassium Pump

Animation?

Ion Channel ReceptorsIon Channel Receptors

You Try! You Try! Structure of Acetylcholine Structure of Acetylcholine (left) and Nicotine (right)(left) and Nicotine (right)

Acetylcholine ReceptorNovember 2005 Molecule of the Month  by David S. Goodsell

2. Protein 2. Protein KinasesKinases: the Insulin : the Insulin ReceptorReceptor

3. G-Protein Linked (coupled) 3. G-Protein Linked (coupled) Receptors- GPCRsReceptors- GPCRs

Over 60% of all Over 60% of all prescription drugs on the prescription drugs on the market, (12 of the top-20) market, (12 of the top-20) selling drugs, directly or selling drugs, directly or indirectly target GPCRs indirectly target GPCRs (=>$200 billion/yr in (=>$200 billion/yr in sales)sales)

Every known GPCR is Every known GPCR is associated with at least associated with at least one commercially one commercially available drugavailable drug

Examples include Examples include Zantac® and Pepcid® Zantac® and Pepcid® (ulcers); and morphine (ulcers); and morphine (pain) (pain)

*Bio-Quant, 2001*Bio-Quant, 2001

Epinephrine nestles in predicted binding site of predicted human 1-adrenergic receptor. [Proc. Nat. Acad. Sci. USA, 99, 12622 (2002)].

GPCR Mechanism: GPCR Mechanism: OverviewOverview

Another Look at G Protein-Another Look at G Protein-Coupled ReceptorsCoupled Receptors

Cytoplasmic Cytoplasmic (Intracellular(Intracellular) Receptors) Receptors

Signal Transduction: DirectSignal Transduction: Direct

Signal Transduction: Signal Transduction: IndirectIndirect

Signal Transduction: Protein Kinase Signal Transduction: Protein Kinase CascadeCascade

Critical Functions:1.Amplifies Signal2.Communicates to the Nucleus3.Multiple steps provides Specificity

Example: RASExample: RAS

Second Second MessengerMessenger

s: s: Sutherland’Sutherland’

s s HypothesisHypothesis Small, nonprotein, Small, nonprotein, water-soluble water-soluble molecules/ions molecules/ions that relay a signalthat relay a signal

Rapidly spread a Rapidly spread a signal through the signal through the cell via diffusioncell via diffusion

Common Second Messengers:Common Second Messengers:

Cyclic AMP (cAMP)Cyclic AMP (cAMP)

cAMP tends to bind to ion channels, opening them, and protein kinases, activating them.

Phospholids can be hydrolized Phospholids can be hydrolized to form second messengersto form second messengers

Example: Phosphatidyl inositol-bisphosphate (PIP2)Example: Phosphatidyl inositol-bisphosphate (PIP2)

Other Common Second Other Common Second Messengers: CaMessengers: Ca2+2+

A wave of calcium ions

spreads through an

egg in response to fertilization.

Image: http://dept.kent.edu/biology/kline/cawave.htm

Other Other Common Common Second Second

MessengerMessengers: Cas: Ca2+2+

Two or More Second Two or More Second Messengers May Work Messengers May Work

TogetherTogether

Other Cool Second Other Cool Second Messengers: Nitric OxideMessengers: Nitric Oxide

““NO news is good NO news is good news.”news.”

Other Cool Second Other Cool Second Messengers: Nitric OxideMessengers: Nitric Oxide

Viagra…Viagra…

Other Modes: Direct Other Modes: Direct Communication Between CellsCommunication Between Cells

Other Modes: Direct Other Modes: Direct Communication Between CellsCommunication Between Cells