• Transduce chemical signals into electrical signals
• Allow for rapid response
• Important for electrically excitable cells such as nerves or muscles

Function

1. Channel protein in closed conformation so ions cannot pass
2. Ligand binds to ligand binding site
3. Channel protein changes to open conformation so ions can now pass and cause a cellular response
4. Ligand leaves
5. Channel changes back to closed conformation and ions can no longer pass

Role of Ligand-gated Ion Channel in Synaptic Transmission

1. Action potential travels down presynaptic axon
2. Cargo vesicle fuses with presynaptic plasma membrane and releases neurotransmitters
3. Neurotransmitters (ligands) bind to ligand-gated ion channel in postsynaptic cell membrane opening the channel
4. When enough ions pass into the postsynaptic cell, voltage-gated ion channels open
5. More ions pass through these channels, further changing the membrane voltage and opening voltage-gated channels further along the membrane
6. This depolarization (action potential) travels along the membrane to the next synapse continuing the signal transmission

Types of Ligand-gated Ion Channels

Excitatory

• Na+ channels – allow positive ions into the cell depolarizing the membrane and driving it closer to firing an action potential

Inhibitory

• Cl- channels – allow negative ions into the cell making it harder for the membrane to depolarize
• K+ channels – allow positive ions out of the cell making it harder for the membrane to depolarize

• Transduce signals into electrical signals
• Allow for rapid response

3 TYPES

1) Ligand-gated Ion Channels

• Specific ligand is required for each channel
• Ligand binds to ligand binding site on channel
• Channel opens allowing ions to pass through
• When ligand dissociates, channel closes

2) Mechanically-gated Ion Channels

• Physical (i.e., stretching) forces on the membrane or channels are what open the channels and allow the ions to traverse the membrane

3) Voltage-gated Ion Channels

Sodium & Potassium Channels

a) Sodium Channel

• Change in membrane potential opens the channel – activation gates change to the open conformation and sodium can traverse the membrane
• Channel becomes inactivated – Inactivation gate “plugs” the channel and sodium cannot travel through the membrane
• Channel eventually resets back to closed conformation

b) Potassium channel

• Change in membrane potential opens the channel – activation gates change to the open conformation and potassium can traverse the membrane
• Channel eventually resets back to closed conformation

Receptor

Molecule allowing a cell to recognize a message and respond to it

Ligand

Molecule that specifically binds to another molecule

Cell Junctions

• Local signaling
• Use gap junctions
• Signals can bypass cell membrane

Direct Contact

• Local signaling
• Requires cell to cell contact
• Signal molecule bound on cell membrane
• Signal molecule on one cell binds to receptor molecule on another cell

Paracrine

• Local signaling
• Cell releases soluble signal molecules into the extracellular space
• Signals diffuse from releasing cell and reach target cell

Synaptic

• Local signaling
• Allows neurons to pass signals to other cells
• Use neurotransmitters as signal molecules

Endocrine

• Long distance signaling
• Signals travel through blood vessels before reaching target cell
• Insulin released by pancreas into bloodstream causes cells all over the body to absorb glucose from the bloodstream

• Programmed cell death
• Specific biochemical signature (ex. phosphatidylserine “flips” to outer surface of plasma membrane)
• Does not induce inflammation

Important in a Variety of Processes

• Organism development
• Cell number and organ size
• Quality control during development
• Removal of damaged cells

Cellular Changes

• Cytoplasm condenses
• Nucleus becomes misshapen
• Chromatin condenses along the nuclear envelope
• Cell eventually fragments into blebs
• Phosphatidylserine on the blebs indicates to phagocytic cells that apoptosis is occurring
• Phagocytic cells clear the cellular debris

Two Paths of Apoptosis

1. Extrinsic Pathway (using the Fas pathway as an example)

a) Trimeric Fas ligand on another cell binds to Fas death receptor
b) Intracellular domain of Fas receptor recruits and activates FADD (Fas associated death domain)
c) Activated FADD recruits initiator procaspases such as procaspase-8 or -10 (complex is referred to as death-inducing signaling complex or DISC)
d) Complex formation activates the procaspases which then activate executioner caspases
e) Executioner caspase activation leads to apoptosis

2. Intrinsic Pathway

a) Apoptotic stimulus activates BH3-only protein
b) BH3-only protein blocks the activity of Bcl-2 protein
c) Without Bcl-2 activity, BH123 proteins are able to oligomerize and cytochrome c is released from the intermembrane space of mitochondria
d) Cytochrome c in the cytoplasm activates Apaf1 proteins which form a heptameric complex
e) Apaf1 complex recruits initiator procaspase-9
f) Activated caspase-9 activates executioner caspase
g) Executioner caspase activation leads to apoptosis

Bcl-2 Family of Proteins

• Based on which specific domains are present in the protein

1. Anti-apoptotic Bcl-2 proteins (ex. Bcl-2 or Bcl-XL)
2. Pro-apoptotic BH123 proteins (ex. Bax or Bak)
3. Pro-apoptotic BH-3 proteins

PLASMA MEMBRANE

• Often called phospholipid bilayer
• Comprises: Proteins, Cholesterol, Carbohydrates.
• Separates cell from external environment; controls the flow of material into and out of it.

CYTOSOL

• Aqueous solution that bathes organelles and contains a variety of molecules
• Portion of cytoplasm not contained within organelles
• Free ribosomes

ENDOMEMBRANE SYSTEM

• Select group of membranous organelles that regulate protein trafficking and metabolism

NUCLEUS

• Nuclear envelope with pores (double-membrane)
• Site of DNA replication and RNA synthesis (transcription)
• Contains: chromatin, nucleolus (rRNA and ribosomal proteins)

ENDOPLASMIC RETICULUM

• Continuous with nuclear envelope
• Cisternae enclose a space called the ER lumen
• Rough ER: with bound ribosomes; site of protein synthesis, processing and secretion
• Smooth ER: no ribosomes; lipid synthesis, carbohydrate metabolism, detoxification

TRANSPORT VESICLE

• Keeps secretory proteins separate from proteins synthesized in the cytosol

GOLGI APPARATUS

• cis side faces the nucleus, trans side where cargo exits
• Modifies, stores and secretes molecules that it receives from the ER
• Synthesizes its own macromolecules

LYSOSOME

• Vesicle that contains hydrolytic enzymes; digests endosomal cargo

ENDOSOME

• Forms when cell engulfs nutrients or other particles via endocytosis

RIBOSOMES

• Two subunits: one large and one small
• Synthesize proteins via translation
• Can be bound to rough ER or free (suspended in cytosol)

MITOCHONDRION

• Double-membrane bound: inner membrane invaginates to form cristae
• Space within cristae: matrix (contains free ribosomes)
• Space between inner and outer membranes: intermembrane space
• Synthesizes ATP via citric acid cycle and oxidative phosphorylation (couples oxidation of nutrients with ADP phosphorylation)

PEROXISOME

• Single-membrane bound vesicle
• Produce hydrogen peroxide from detoxification of substances (i.e. alcohol)

CYTOSKELETON

• Microfilaments, intermediate filaments and microtubules
• Anchors organelles and provides structural framework

CENTROSOME

• Where microtubules nucleate
• Contains two small structure called centrioles
• Functions in cell division

DOUBLE MEMBRANE BOUND ORGANELLES

• Nucleus
• Mitochondria

CLINICAL CORRELATIONS

• Rough ER Network and Pancreatic beta cells
  – Specialize in synthesizing and secreting the peptide hormone insulin; large rough ER network proportional to their secretory activity
• Smooth ER and Hepatic cells
  – Drugs and/or alcohol can induce the proliferation of smooth ER, which accelerates detoxification
• Lysosomes and Tay-Sachs disease
  – Lysosomal storage disease that presents when lysosomes are missing a lipid-digesting enzyme (or its active form)
  – Lipids accumulate in cells because lysosomes cannot digest them; impair brain function

Middle compartment has a sac-like shape; it houses the pericardium, heart, and roots of the great vessels.
Anterior compartment lies anterior to this, and extends from the sternal angle, superiorly, to the diaphragm, inferiorly.
Posterior compartment lies posterior to the middle mediastinum, and, like the anterior mediastinum, extends from the sternal angle to the diaphragm.
Superior mediastinum fills the space between the superior thoracic opening to the sternal angle.

Key anatomical structures

• The thymus lies within the superior and anterior regions; recall that this structure regresses after childhood.
• Then, return to where the root and ascending portion of the aorta arise in the middle mediastinum, and show that the aorta continues through the superior and posterior compartments. We’ve also shown the branches of the aortic arch as they extend through the superior mediastinum.
• Next, posterior to the heart, show the opening of the left pulmonary artery as it passes to the left lung;
• The opening of the left bronchus; indicate that the trachea extends through the superior and posterior compartments of the mediastinum.
• The esophagus also passes through these compartments.

Pathology

• Let’s indicate some key masses that can develop in the mediastinum; we’ll broadly categorize these by region of the mediastinum, but beware of overlap.
• Anterior/superior mediastinum: thymoma, germ cell neoplasm, and lymphoma.
• Middle mediastinum: pericardial cysts, bronchogenic cysts, lymph node enlargement, carcinoma, and lymphoma.
• Posterior compartment: watch for neurogenic tumors and diaphragmatic hernias.

Summary Table

Superior compartment:

• Thymus, esophagus, and trachea.
• The aortic arch and its branches.
• The superior vena cava, brachiocephalic veins, and the arch of the azygos vein.
• The thoracic duct.
• The vagus nerves, recurrent laryngeal nerves, phrenic nerves, and cardiac nerve.

Anterior mediastinum:

• Thymus.
• Branches of the internal thoracic arteries and veins, and, the parasternal lymph nodes.

Middle mediastinum:

• The heart and the roots of the great vessels.
• The ascending aorta, pulmonary trunk, and pericardiacophrenic arteries.
• The superior vena cava, pulmonary veins, and pericardiacophrenic veins.
• And, the vagus nerves, phrenic nerves, and sympathetic nerves.

Posterior mediastinum:

• The esophagus.
• Thoracic aorta.
• Azygos, hemiazygos, and accessory hemiazygos veins.
• The thoracic duct.
• The vagus nerves and sympathetic nerves.

• The larynx is the start of the lower respiratory tract.
• Superiorly, the larynx is attached to the hyoid bone via connective tissues.
• Three key functions of the larynx:
• It conducts air from the pharynx to the trachea.
• It prevents food and liquid from entering the lower respiratory tract.
• It facilitates the production of speech.

Key anatomical structures:

Three larger, singular cartilages:

• Thyroid cartilage – forms anterior and lateral walls; features the laryngeal prominence.
• Cricoid cartilage – circular, forms base of larynx.
• Epiglottis – “flap” that attaches to the internal surface of the thyroid cartilage, anteriorly, and projects posteriorly and superiorly over the opening of the larynx.
  • Upon swallowing, the flap closes off the entryway to the larynx, which prevents foods and liquids from entering the lower respiratory tract.

Three paired sets of smaller cartilages:

• Arytenoid cartilage – articulates with cricoid cartilage posteriorly.
• Corniculate cartilage – sits on arytenoid cartilages.
• Cuneiform cartilage – sits anterior to corniculate cartilages; very small, wedge-shaped.

Membranes and connective tissues:

• Thyrohyoid membrane – connects the thyroid cartilage and hyoid bone.
• Cricothyroid ligament – extends superiorly from the cricoid cartilage to the thyroid and arytenoid cartilages.
• Vocal ligament – thickened superior edge of the cricothyroid ligament comprises the vocal ligament; known as the “true” vocal cord because it facilitates sound production.
• Rima glottides – opening between the vocal cords. During sound production, laryngeal muscles contract to rotate the arytenoid cartilages and alter the opening between the true vocal cords.
• Quadrangular membrane – connects the lateral sides of the epiglottis to the arytenoid cartilages.
  • Free edges of the quadrangular membrane thicken to form the:
    Aryepiglottic ligament, superiorly
    The vestibular ligament, inferiorly

The vestibular ligament and its mucosal covering are often referred to as the “false vocal cord”; it does not participate in sound production.

Clinical correlations:

Laryngitis is inflammation of the vocal cords, which can stem from infectious or non-infectious causes (such as over-use). It typically results in hoarseness but severe swelling can block the airways.

LUNGS

• The primary function of the lungs is to facilitate gas exchange between the body and the external environment.
• The lungs occupy most of the thoracic cage:
  * The apex of the lung, its most superior portion, reaches the first rib.
• The base of the lung, its inferior concavity, rests on the diaphragm.
• The mediastinum, which is the space between the lungs, houses the heart.

Right lung:

• 3 lobes (superior, middle, inferior)
• 2 fissures:
  • HORIZONTAL fissure separates the superior and middle lobes.
  • OBLIQUE fissure separates the middle and inferior lobes.

Left lung:

• 2 lobes (superior, inferior)
• 1 fissure:
  • OBLIQUE fissure separates the middle and inferior lobes.

The left lung is smaller than the right because the heart lies slightly to the left within the thoracic cage.

Specifically, the heart nestles within the cardiac impression of the left lung, which is visible as the cardiac notch in anterior view.

Membranes:

The lungs are enclosed by the double-layered pleural sac:

• Visceral pleura forms the outermost layer of the lungs
• Parietal pleura lines the pulmonary cavities.
• Pleural cavity lies between the visceral and parietal pleura; it contains a small film of serous fluid that reduces friction between the layers.

Root of lung:

Pulmonary vessels and the bronchi anchor the lung within the mediastinum.

• Medial aspects of lungs.
• Hilum is obliquely shaped area, is lined by the pleural sleeve (aka, mesopneumonium).

Clinical Correlations:

• Pleurisy is infection of the pleura and causes chest pain upon breathing or coughing.
• Pneumothorax occurs when a ruptured pleural sac allows air to enter the thoracic cavity; the lungs collapse due to pressure changes.

Key structures:

Trachea:

• Cartilaginous “trunk” of the tree.
• Comprises 15 – 20 C-shaped cartilaginous rings, are stacked vertically and connected via anular rings.
• Trachealis posterior forms posterior wall of trachea; moves to accommodate foods passing posteriorly through the esophagus.

Bronchi:

• Primary bronchi enter the lungs.
• Secondary bronchi serve lobes of lung (“lobar” bronchi).
• Tertiary bronchi serve bronchopulmonary segments (“segmental” bronchi); 10 on the right, 8-10 on the left.

Bronchioles:

• Numerous, and narrow as they branch.
• Have more smooth muscles in their walls, but still have cartilage in their walls.
• Terminal bronchiole is the final passageway of the conduction portion of the respiratory system.

Respiratory bronchioles:

• Demarcate the respiratory portion of the respiratory tract.
• Thin walls allow some gas exchange.

Alveolar ducts:

• Arise from respiratory bronchioles.

Alveolar sacs:

• Terminal ends of the alveolar ducts.

Alveoli:

• Thin-walled out-pockets of the alveolar sacs.
• Surrounded by pulmonary capillaries.
• Facilitate gas exchange between the respiratory and cardiovascular systems.

Lungs:

• Hundreds of millions of alveoli.
• Left lung = superior and inferior lobes; heart nestles into medial left lobe.
• Right lung = superior, middle, and inferior lobes.

Clinical Correlations:

Lung cancer often originates in the bronchi.
Pulmonary embolism (aka PE) obstructs arterial supply. In a PE, gas exchange is reduced, and blood oxygen levels drop.

• Begins at the nose and ends with the pharynx.

Anatomical Structures

Nose:

• Opens the respiratory system to the external environment via the nostrils (aka, nares).
• Comprises bone and cartilage.

Nasal cavity:

• Posterior to the nose.
• Separated from the oral cavity by the hard and soft palates:
  • The hard palate comprises the maxillary and palatine bones.
  • The soft palate comprises soft tissues.
• Olfactory cells line the superior part of the nasal cavity
• The nasal septum divides the cavity into right and left sides.
  • It comprises two vertical bony structures: the perpendicular plate of the ethmoid bone superiorly and the vomer, inferiorly.
  • A deviated nasal septum can obstruct airflow and cause sinusitis (sinus infection), epistaxis (nose bleeds), anosmia (inability to smell), and other health problems.
• 3 nasal conchae: superior, middle, and inferior.
  • Bony projections that arise on the lateral walls of the nasal cavity.
  • The nasal conchae create meatuses (superior, middle, and inferior), which are small tunnels.
  • Movement of air around the conchae and through the meatuses creates turbulence, which helps to warm and humidify the air. Hence, the conchae are sometimes referred to as the “turbinate” bones.

Paranasal sinuses

• Spaces within the bones surrounding the nasal cavity.

Pharynx:

• Descends posterior to the nasal cavity, oral cavity, and larynx, and is open to each of these structures.
• Common passageway foods/liquid and air: it serves both the respiratory and digestive systems.
• 3 subdivisions:
  • Nasopharynx: posterior to the nasal cavity (and receives air from the nasal cavity).
    The choanae are the openings between the nasal cavity and the nasopharynx.
    Oropharynx: posterior to the oral cavity (and receives foods and liquids from the oral cavity).
    The fauces is the opening between the oral cavity and the oropharynx.
  • Laryngopharynx: posterior to the larynx (it is the final common passageway for air and food/liquid).
• The auditory tube (aka, Eustachian or pharyngotympanic tubes) opens into the nasopharynx
  • Connects the ears and throat, which allows infection to pass between them.
  • Auditory tube inflammation occurs in otitis media (aka, ear infection), which is common amongst children.

Tonsils

• Collections of lymphoid tissues that participate in immunological defense against bacterial and viral infections.
• 3 pairs of extrinsic tonsils:
  • Pharyngeal tonsils reside in the superior wall of the nasopharynx.
  • Palatine tonsils are near the palate (hence, their name).
  • Lingual tonsils are at the back of the tongue (“lingual” refers to the tongue).
• As part of an aggressive immune response, the tonsils can swell and block airflow through the nose or inhibit swallowing.
  • Chronic infection may necessitate tonsillectomy.