6: Cell Signaling

Catabolism

Breakdown of large molecules

Anabolism

Uses energy to build molecules

Functions of the ER

Proteins enter ER during synthesis; vesicles move proteins ER→Golgi; N-terminal signal = ER destination; folding required for secretion; continuous with rough ER; glycosylation holds proteins until folded

Three mechanisms for protein transport inside a cell

(1) Cytosol ↔ Nucleus via nuclear pores, NLS, GTP hydrolysis;

(2) Cytosol → Mitochondria/ER/Peroxisomes via signal sequences, translocators, unfolding;

(3) ER → Endomembrane system via vesicular transport (clathrin, adaptin, dynamin, Rab, SNAREs)

Mitochondria function

ATP synthesis

Endosome function

Sorting endocytosed molecules

Lysosome function

Intracellular degradation

Peroxisome function

Oxidation reactions

Free ribosome function

Protein synthesis in cytosol

Nucleus function

Genome storage, DNA/RNA synthesis

ER function

Lipid & protein synthesis

Golgi function

Modify, sort, package proteins/lipids

Zellweger syndrome cause

Peroxisome defect (PEX mutation) → failure to import proteins → degeneration of brain, liver, kidney

Zellweger syndrome symptoms

Hypotonia, hepatomegaly, seizures, poor feeding, early death (<6 months)

Cystic fibrosis cause

CFTR mutation → misfolded protein degraded in ER → defective Cl⁻ transport

Cystic fibrosis symptoms

Thick mucus in lungs, digestive problems, chronic infections

Familial hypercholesterolemia cause

Mutations in LDL receptor → defective receptor-mediated endocytosis → cholesterol buildup

Familial hypercholesterolemia symptoms

High cholesterol (>1000 mg/dL), early atherosclerosis, heart attack risk

Functions of coat proteins

Clathrin (vesicle coat); Adaptin (secures clathrin, selects cargo); Dynamin (pinches vesicle, GTPase)

Function of Rab proteins

GTP-binding proteins on vesicles recognized by tethering proteins

Function of tethering complex

Recognizes Rab, docks vesicle

Function of SNAREs

v-SNARE + t-SNARE fuse vesicle to membrane

Structure of Golgi

Stack of cisternae; cis face (entry, near ER), trans face (exit, toward plasma membrane)

Protein transport direction through Golgi

ER → cis Golgi → through cisternae → trans Golgi → PM/lysosome

Constitutive vs regulated exocytosis

Constitutive = continuous, no signal; Regulated = requires external signal (e.g., insulin release)

Secretory vs endocytic pathway

Secretory: ER→Golgi→PM/lysosome; Endocytic: molecules ingested → endosome → lysosome

Phagocytosis vs pinocytosis

Phagocytosis = cell eating large particles; Pinocytosis = cell drinking fluids

Cells that perform phagocytosis

Macrophages, neutrophils, monocytes, dendritic cells

Receptor-mediated endocytosis definition & example

Selective uptake via receptors (e.g., LDL uptake)

Clinical correlate of receptor-mediated endocytosis

Familial hypercholesterolemia (defective LDL receptor)

Lysosome functions

~40 hydrolytic enzymes, acidic pH (5), ATP-driven H⁺ pump, degrade & recycle macromolecules

Three fates of endocytosed receptors/cargo

Recycle, Degrade, Transcytosis

General principles of cell signaling

Signal + receptor = cascade; cascades relay, amplify, integrate, distribute, feedback regulate

Early vs late cell responses

Early/fast = no new proteins (movement, secretion, metabolism); Late/slow = gene expression (growth, division)

Four main signaling types

Endocrine (hormones, blood); Paracrine (local mediators); Synaptic (NTs); Contact-dependent (direct); (+Autocrine)

Positive feedback

Amplifies signal (e.g., lactation)

Negative feedback

Dampens signal (e.g., baroreflex)

Molecular switches

Phosphorylation (kinases/phosphatases) or GTP-binding proteins (GDP = inactive, GTP = active)

Intracellular vs cell-surface receptors

Intracellular: hydrophobic ligands (steroids, NO), regulate transcription; Cell-surface: hydrophilic ligands (peptides, NTs)

Cortisol pathway

Cortisol crosses membrane → binds receptor → conformational change → nucleus → gene transcription

Nitric oxide pathway

ACh → NO synthase → NO diffuses → activates GC → GTP→cGMP → smooth muscle relaxation

Nitroglycerin mechanism

Converted to NO → activates GC → ↑cGMP → smooth muscle relaxation → treats angina

Ion-channel coupled receptors

Ligand opens channel → ion flow → electrical signal (e.g., ACh receptor)

Structure of GPCR

7-pass transmembrane protein; activates G-proteins

Gs signaling cascade

Gs → AC → ↑cAMP → PKA activation → phosphorylation

Gi signaling cascade

Gi → inhibits AC → ↓cAMP → inhibits PKA

Gq signaling cascade

Gq → PLC → PIP₂ → IP₃ (↑Ca²⁺) + DAG (activates PKC)

GPCR ion channel mechanism

G protein directly opens ion channel

GPCR vs enzyme-coupled receptors

GPCR = 7-pass, trimeric G proteins; Enzyme-coupled = 1-pass, ligand binding → dimerization + kinase activity

Ras function

Small GTP-binding protein downstream of RTKs; controls growth/differentiation

Ras mutation in cancer

Mutation blocks GTP hydrolysis → Ras always active → uncontrolled proliferation (~30% cancers)

Clinical correlate of phagocytosis

Mycobacterium tuberculosis prevents fusion of phagosome with lysosome → survives inside macrophages

Mechanism for Phagocytosis

1. Coronin1 -> increases Ca2+

2. Ca2+ increase causes calcineurin

3. Calcineurin inhibits phagosome fusion with lysosome