Plasma Membrane Receptors I.

Receptor-ion channel (RIC) o If the RIC is a Na/K channel, this will cause a change in membrane potential. Change in MP initiates entry of Ca via voltage gated Ca channel. Ca acting as 2nd messenger binds to calmodulin which then activates the downstream proteins leading to a cellular response. o If the RIC is a Ca channel, it basically functions as a ligand gated Ca channel. Opening of the channel causes entry of Ca. Ca acting as 2nd messenger binds to calmodulin which then activates the downstream proteins leading to a cellular response. Receptor-enzyme (RE) Tyrosine Kinase Guanylyl Cyclase o Ligand binding causes activation of o Ligand binding causes activation of the receptors enzymatic portion. RE complex. o Autophosphorylation (receptor o RE complex cleaves or phosphorylates own tyrosine dephosphorylates GTP to form groups). cGMP. o Phosphotyrosine formed serves as a o cGMP acts as 2nd messenger which docking site for downstream activates PKG. proteins. o PKG activates downstream proteins o A downstream protein is activated leading to cellular response. once it binds to the docking site. This leads to a cascade of protein activation ending in a cellular response.

II.

Concepts in Ligand-Receptor Binding SPECIFICITY ability of receptor to bind exclusively to a limited number of structurally related types of chemical messenger. If a chemical messenger is released in the blood stream, it s going to bind to the cells which only contain the ligands specific receptor. Common ligands: o Acetylcholine (cholinergic) receptors nicotinic & muscarinic Muscarinic Receptor Type Location Postreceptor mechanism M1 Nerves IP3-DAG formation M2 Heart cAMP inhibition K channel activation M3 Glands & Smooth muscle IP3-DAG formation M4 CNS cAMP inhibition M5 CNS IP3-DAG formation Nicotinic Receptor Type NM NN o Location Skeletal muscle Postganglionic cell body Postreceptor mechanism Na/K channel activation Na/K channel activation

Epinephrine & Norepinephrine (adrenergic) alpha & beta Adrenergic Receptor Type Postreceptor mechanism A1 IP3-DAG formation

A2 B1 B2 B3

cAMP inhibition cAMP formation cAMP formation cAMP formation

SATURATION percentage of total number of specific receptor that is occupied by messengers. AFFINITY strength to which a chemical messenger binds to a receptor. COMPETITION ability of different molecules that are structurally similar to fight each other to combine with the same receptor.

AGONIST chemical messenger that binds to a receptor and triggers the cells response. ANTAGONIST molecule that competes for a receptor with a chemical messenger normally present in the body. It binds to the receptor but does not trigger the cells response. DOWN-REGULATION adaptation of the cell wherein the total number of plasma membrane receptors is diminished due to a chronic high concentration of its ligand. UP-REGULATION - adaptation of the cell wherein the total number of plasma membrane receptors is increased due to a chronic low concentration of the ligand.

III.

Receptors that activate G-Protein

G-protein type Effector protein cAMP Gs/Gi Adenylyl Cyclase cGMP Gt Phosphodiesterase IP3/DAG Gq Phospholipase C Arachidonic Acid Phospholipase A

2nd messenger Protein kinase

cAMP PKA

cGMP PKG

IP3/DAG PKC Ca-calmodiulin Dependent kinase

Arachidonic acid Prostacyclin Thromboxane Prostaglandin Leukotrienes ETE

IV.

Components of Signal Transduction pathway that is initiated by the GPCR stimulation are the following: 1. Ligand of the 1st messenger 2. Receptor 3. G-Protein 4. Effector Protein 5. 2nd messenger 6. Protein kinase 7. Downstream proteins 7 Steps 1. ligand binding 2. G-protein attaches to receptor 3. GTP replaces GDP

V.

4. 5. 6. 7. VI.

G-protein detaches/disassembles Subunits attach to effector protein GDP replaces GTP Reassembling G-protein (inactivated)

Calcium as 2nd messenger a. 2 sources a. Extracellular fluid b. Endoplasmic reticulum b. ECF Ca enters via: a. Voltage gated ion channel b. Ligand gated Ca channel c. 2nd messenger induced opening of Ca channel c. Endoplasmic Ca release in response to a. IP3 b. Ca induced calcium release d. In most cells, cytosolic Ca binds to and activates calmodiulin a. The activated Ca-calmodiulin complex activates a calmodiulin dependent protein kinase (CDPK). CDPK activates other downstream effectors and leading to a cellular response