UNIT FIVECHAPTER 9

CELL COMMUNICATIONCHAPTER 9

OVERVIEW

• Communication between cells is critical to survival

• Cell signaling requires a signaling molecule, or ligand, and a receptor protein to function

• Interaction between the ligand and receptor is called signal transduction

• The result of transduction is cellular response

TYPES OF SIGNALS

• Peptides

• Large proteins

• Amino acids

• Nucleotides

• Steroids

• Lipids

• Nitric oxide

HOW DOES THIS WORK?

• Shape of the ligand and the receptor need to be complementary

• Binding induces a shape or conformational change

• Conformation change produces a cellular response

FOUR TYPES OF SIGNALINGDetermined by distance from source to receptor

Fifth type—autocrine—cells send signals to themselves

WHY HAVE SIGNALING?

• To produce a response

• The key to producing the response is phosphorylation

• Phosphorylation of proteins alters their function and essentially turns them “on” or “off”

PROTEIN KINASES AND PHOPHATASESProtein kinases add a phosphate

The phosphate attaches to the –OH group of either serine, threonine, or tyrosine

Two classes: serine-threonine kinases and tyrosine kinases

Phosphatases reverse the action of protein kinases

RECEPTORS ARE DEFINED BY LOCATION

• Intracellular receptors bind hydrophobic ligands

• Cell surface or membrane receptors bind hydrophilic receptors

MEMBRANE RECEPTORS

SECOND MESSENGERS

• Membrane proteins sometimes utilize other cytoplasmic substances to relay messages

• The substances can be ions or other small molecules, but they are referred to as second messengers

• Cyclic adenosine monophosphate (cAMP)

• Calcium ions (Ca+2)

INTRACELLULAR RECEPTORS

• Small lipid soluble molecules can pass through the membrane

• Steroids are one of the simplest and most direct intracellular receptors

• Cortisol

• Estrogen

• Progesterone

• Testosterone

STEROID RECEPTOR ACTION

• Primary function of steroid receptors is to regulate gene expression

• Each receptor has three functional domains

• Hormone-binding domain

• DNA-binding domain

• Domain to interact with coactivators to regulate level of gene transcription

ROLE OF COACTIVATORS

• Large number of coactivators

• Receptors can interact with many coactivators eliciting different responses

• Estrogen has different effects in uterine vs. mammary tissue, the difference is due to coactivators

OTHER INTRACELLULAR RECEPTORS

• Guanylyl cyclase binds NO allowing it to catalyze the synthesis of cyclic guanosine monophosphate (cGMP), which can cause muscle relaxation

• Acetylcholine binds epithelial cells causing a release of Ca+2 that stimulates NO production that causes cGMP production to relax epithelial smooth muscle

• Sildenafil or Viagra function using the cGMP pathway

SIGNAL TRANSDUCTION THROUGH RTKS

• Receptor tyrosine kinases (RTKs)

• Influence: cell cycle, metabolism, cell migration, cell proliferation, virtually all aspects

• Alterations to RTK function can result in cancer

• Receptors can get stuck in the “on” position

• Plants have similar receptors, Serine-Threonine Kinases

RTKS FUNCTION THROUGH PHOSPHORYLATION

THE INSULIN RECEPTORDocking proteins are exemplified by the insulin receptor

Insulin response protein binds to the phosphorylated receptor

Signal passed from the response protein to glycogen synthase

Glucose gets converted to glycogen thereby lowering blood sugar

ADAPTER PROTEINSA class of proteins that bind phosphotyrosines

Do not participate in signal transduction, but act as a link between receptors and downstream events

RAS

CASCADES CAN AMPLIFY SIGNALS

• Mitogen activated protein kinases (MAP kinases)

• Mitogen is a chemical that stimulates cell division

• MAP kinases are activated by a phosphorylation cascade or kinase cascade

• Amplification comes from the ability of the enzymes to run the reactions over and over—small number of molecules give a large response

SCAFFOLD PROTEINS

• Used to organize cascades in the cytoplasm to increase effectiveness

• Physically arranged sequence is more efficient than a sequence that relies on diffusion to move molecules

• Disadvantage—reduces amplification

CLOSER LOOK AT RAS

• It is the link between RTK and MAP kinases

• It is a small GTP binding protein

• Active when bound to GTP and inactive when bound to GDP

• RAS is mutated in many human tumors

• Works by exchanging GDP for GTP through GEFs (guanine exchange factors)

• Can be terminated by GTPase activity, which is controlled by GAP proteins

RTK INACTIVATION

• Two methods of turning “off” RTKs

• Dephosphorylation

• Internalization—receptor is taken up by vesicle and degraded and recycled

G PROTEIN COUPLED RECEPTORS (GPCR)

• Single largest category of receptors in animal cells

• Diverse ligands: ions, organic odorants, peptides, proteins, lipids, photons

• Seven transmembrane domains

• Found in virtually all eukaryotic cells

• Latest count, 799, about half involved in taste and smell

• In mice, 1000, with five subgroups

LINKING RECEPTORS AND EFFECTORSGPCRs are the link between the receptor and the effector proteins that elicit responses

Acts as a switch, when “on” the effectors can cause a cellular response

EFFECTORS CAN PRODUCE MULTIPLE RESPONSES

• Many effectors activated by G proteins have multiple responses due to second messengers

• Common second messengers:

• Adenylyl cyclase-produces cAMP and IP3

• Phospholipase C—produces DAG

CYCLIC AMPcAMP activates protein kinase A (PKA), which adds phosphates to other proteins

Effect depends on cell type

In muscle cells PKA cause glucose to manufactured and glycogen production to be inhibited

Vibrio cholera produces a toxin to turn “on” GCPR, causing large cAMP production, increased Cl- ions to leave the intestine and bring water with them, result: diarrhea

INOSITOL PHOSPHATES AND CALCIUM

INOSITOL PHOSPHATES

• Most common is PIP2

• Substrate of effector protein phospholipase C, which

cleaves PIP2 to make DAG

and IP3

CALCIUM

• Ca+2 ions are normally low in cytoplasm, but high in the ER

• IP3 can be bound by ER receptor to release Ca+2

CALMODULIN

• Ca+2 can bind a 148 amino acid protein called calmodulin

• When 4 Ca+2 ions bind then calmodulin can activate other proteins• Protein kinases

• Ion channels

• Cyclic nucleotide phosphodiesterases