Human Physiology pt 1

What are the 4 general categories of specialized cells? Give a general description for each

1. epithelial cells

   • found at surface of body or hollow organ

   • specialized to secrete or absorb ions/organic molecules

2. connective tissue cells

   • form extracellular elements

   • connect, anchor, and support body structures

3. neurons

   • highly specialized cells for rapid communication

   • initiate, integrate, and conduct electrical signals

4. muscle cells

   • electrically excitable

   • key feature is that they can change their shape based on actin and myosin filaments that generate force and movement

What are tissues, organs, and organ systems?

• tissues = collections of cells that carry out related functions

• organs = collections of multiple tissue types that carry out related functions

• organ systems = collections of multiple organs that work together

What are the 10 physiological organ systems in the body?

1. integumentary system

   • skin

   • one of 2 barriers between you and outside world

   • forms a protective boundary that separates the body’s internal environment and external environment

2. digestive system

   • the other barrier between you and outside world; tube that takes outside world through the body essentially

   • takes up nutrients and water and eliminates wastes

3. reproductive system

   • produces eggs or sperm

4. immune system

   • provides defense against foreign invaders

5. endocrine system

   • coordinates body function through synthesis and release of regulatory molecules

   • one of two communication systems in the body

6. nervous system

   • the other communication system in body

   • coordinates body function through electrical signals and release of regulatory molecules

7. circulatory system

   • transports material between all parts of the body

8. respiratory system

   • exchanges O and CO2

9. musculoskeletal system

   • provides support and is responsible for movement

10. urinary system

    • maintains water and solutes in internal environment

    • waste removal

Explain how the outside world affects the cell turnover rate in the integumentary and digestive systems?

• integumentary and digestive systems are the 2 main protective barriers between internal and external environments 

• their cells are so abused by the outside world that they need to keep turning over the cells 

• they keep shedding and creating new cells at a relatively fast rate because of their contact with the outside world

Explain cellular differentiation

• cellular differentiation is a process that happens during development

• a single cell proliferates and those cells become specialized into the 4 functional groups

What is one important way in which cells regulate their own activity?

By maintaining differences in fluid composition across the cell membrane

What is intracellular fluid and what is extracellular fluid?

• intracellular fluid = fluid inside cells

  • distinct from ECF

• extracellular fluid = ECF

  • made of plasma and interstitial fluid

    • interstitial fluid = fluid directly in contact with outside of cells

    • plasma = fluid in blood; flowing around in cardiovascular system

  • serves as buffer zone bw cells and outside environment

What is the interstitium?

The space containing interstitial fluid 

What percent of body weight is water? What percentages are intracellular, plasma, and interstitial volumes?

• 60% of TOTAL body weight is water

• 2/3 of body FLUID is intracellular fluid

• of the remaining 1/3:

  • 20-25% is plasma

  • and remaining 75-80% is interstitial fluid

• another way to think about it is this:

  • 67% of ALL body FLUID is intracellular

  • 26% of ALL body FLUID is interstitial

  • 7% of ALL body FLUID is plasma

How does the ECF serve as a buffer zone bw cells? How is it for red and white blood cells?

• essentially all cells except for RBC and WBC are surrounded by interstitial fluid and the plasma from their nearest blood capillary also does buffering/exchange of materials

• however since RBC and WBC are already in the blood, they aren’t surrounded in interstitial fluid they only have the plasma

• when the ECF composition varies outside its normal range of values, the body has compensatory mechanisms that bring it back to the normal state

  • that is how the intracellular state is controlled/maintained

Compare the composition of intracellular fluid and extracellular fluid

• ICF = higher in protein and potassium (K+)

• ECF = lower in protein but higher in Na+

Compare the compositions of interstitial fluid and plasma

• both are quite similar but plasma has a much higher concentration of protein

  • think bc it has RBC, WBC, and cellular fragments

Why is there a greater difference in composition between ECF and ICF, compared to the difference between interstitial fluid and plasma?

• there is the cell membrane between the ECF and ICF keeping them separate and deciding what passes between them

• there is no such barrier between the interstitial fluid and plasma (blood capillaries are very leaky so they freely allow fluid to pass from one compartment to the other)

What is homeostasis? What is the term for when it is normal and what is the term for when it is not?

• homeostasis = relatively stable condition of internal environment that results from regulatory system actions

• physiology = when homeostasis is normal

• pathophysiology = when homeostasis is not normal

What is dynamic constancy? Give an example

• levels of a certain physiological variable change over short periods of time (dramatically) but over a long period of time they remain relatively constant

• ex)

  • blood sugar remains relatively constant throughout day but then spikes after a meal but then goes back to set point

What is a reflex?

• a specific INVOLUNTARY, unpremeditated, unlearned, built-in response to a particular stimulus

What is a reflex arc? What are the 7 parts of it?

1. stimulus = DETECTABLE change in internal/external environment

   • a change in a physiological parameter

2. receptor = detects stimulus

3. afferent pathway = takes signal from receptor to integrating center

4. integrating center = compares signal to set point and decides what to do next

   • can receive signals from many receptors at a time

5. efferent pathway = takes signal from integrating center to effector

6. effector = muscle or gland that carries out response

7. response = brings back environment to set point (in negative reflex arc at least)

REMEMBER: A comes before E in alphabet → afferent BEFORE efferent

• note actual body parts/organs/glands/etc are bolded; others are more so processes or pathways, etc

What is a negative feedback arc and what is a positive feedback arc?

• negative arc = response acts to counter the stimulus and bring it back to set point → HOMEOSTATIC

• positive arc = response reinforces stimulus and brings further away from set point → NOT HOMEOSTATIC

What is an example of a positive feedback arc/loop?

• childbirth 

  • basically, when a woman is in labor, the baby pushes on cervical stretch receptors which causes a signal to go to brain and indicate that labor has started, to which the brain produces more oxytocin. the oxytocin travels through blood down to uterine lining and causes more contractions, which leads to baby pushing against cervical stretch receptors even more (reinforcement of stimulus)

• in terms of a reflex arc:

  • stimulus: uterus drops and baby’s head pushes on cervical stretch receptors

  • receptor: the cervical stretch receptors

  • afferent pathway takes signal to brain

  • integrating center: hypothalamus → sends efferent pathway

  • efferent pathway → oxytocin, which gets circulated throughout body by vascular system and reaches the effector

  • effector organ = uterine lining

  • response = more contractions and pushing

What are 2 ways in which cells communicate short distance and 2 ways in which they communicate long distance?

1. if target is close:

   1. paracrine = signal diffuses to nearby cells

   2. autocrine = cell sends signal to itself but externally

2. if target is distant:

   1. endocrine = signal travels by blood circulation

   2. neuronal = signal transmitted by nervous system

What are two advantages of intracellular signaling pathways?

1. can amplify a signal → make small signal into big response in cell

2. can allow for tight regulation of pathway → cells can integrate multiple signals

What are 4 potential responses/effects a signaling pathway can cause in a cell?

1. immediate change in metabolism in the cell

   • ex) increased glycogen breakdown when a liver cell detects epinephrine

2. immediate change in electrical charge across plasma membrane 

   • source of action potentials

3. immediate change in regulation of cytoskeletal proteins 

   • affects cellular motility

4. change in transcription → takes more time

What is signal transduction?

• any process by which a cell converts one kind of signal to another

• can take millisecond to a few seconds

• signaling cascade → signal is amplified bc of increasing number of enzymes and second messengers, etc, with every step of the chain

  • can also lead to diversification of outcomes within cell bc of multiple second messengers

What is a second messenger? Give 2 examples

• a molecule (that is not a protein or peptide) that relays signals to target molecules in the cytosol and/or nucleus

• often times, serves to amplify signal

• ex) cyclic nucleotides

  • cyclic AMP → derived from ATP

  • cyclic GMP → derived from GTP

• ex) Ca²⁺

What are the 2 types of extracellular signal molecules? What are the examples we learned for each subcategory?

1. with intracellular receptors

   1. small/hydrophobic enough to cross plasma membrane by self

   2. examples:

      1. Nitric oxide (NO) → gasses can also be signaling molecules

      2. Cortisol → steroid molecules have intracellular receptors bc they are hydrophobic (derived from cholesterol)

2. with extracellular receptors

   1. too big/hydrophilic to cross membrane

   2. 3 types of hydrophilic cell signaling receptors:

      1. G-protein linked receptors

      2. ion-channel linked receptors

      3. enzyme linked receptors

Explain how nitric oxide (NO) works as a signaling molecule?

1. a nerve innervating an endothelial cell of the lumen of a blood vessel has a signal that causes it to release acetylcholine

2. the acetylcholine binds to the receptor of an endothelial cell of the lumen of a blood vessel, which opens gate for Ca²⁺ to enter cell

3. increased Ca²⁺ levels in cell, causes activation of NO synthase, which is the enzyme that breaks down arginine (amino acid) into NO

4. NO is a nonpolar gas molecule, which diffuses rapidly and acts as a paracrine signal to nearby smooth muscle cells of the blood vessel

5. NO enters smooth muscle cells, and activates the guanylyl cyclase, which is the enzyme that converts GTP to cGMP (cyclic GMP)

6. increased cGMP levels leads to dilation of smooth muscle cells by perturbing the cytoskeletal machinery→ causes blood vessel to dilate

   1. only happens in arteries and veins, not in capillaries bc capillaries have no smooth muscle cells

Explain how Viagra works

• Phosphodiesterase (PDE) are the enzymes that break down the cGMP and allow the smooth muscle cells to contract again, so pharmaceutical companies wanted to create a drug that would inhibit PDE so the smooth muscle cells could stay dilated for longer

  • another way this is phrased is that PDE is inhibited so NO signal is prolonged, but Viagra doesn’t actually affect the NO signal pathway by any way it just inhibits PDE so the cGMP isn’t broken down for a longer time

• original plan was to do this as a way to counteract hypertension → PDE inhibited would allow arteries to remain dilated and lower BP

• Pfizer made Viagra for this purpose, but found there are multiple types of PDE in the body, and the one that Viagra inhibited is found only in the male reproductive organ

• Viagra inhibits that specific PDE and counteracts erectile dysfunction by allowing smooth muscle to remain dilated for longer

How do steroid hormones work as signaling molecules? Give 4 examples

• all steroid hormones are derived from cholesterol and have the nonpolar ring structures allowing them to pass through plasma membrane easily

• the receptors for many of these steroid hormones are transcription factors

• process:

  • steroid hormones pass through plasma membrane and bind to transcription factor receptors

  • the steroid receptor complex then moves into nucleus and binds to regulatory region of the target gene and either activates or inhibits transcription of that gene

• ex) cortisol, estradiol, testosterone, and thyroid hormones

Where are hydrophilic cell signaling receptors found in a cell? What are the 3 types of hydrophilic cell signaling receptors?

• found on cell-surface (extracellular side of plasma membrane)

• 3 types

  1. G-protein linked receptors

  2. Ion-channel linked receptors

  3. Enzyme linked receptors

What are G-protein linked receptors?

• largest family of cell-surface receptors

• many types of G-protein receptors → specific to ligand

• all have trimeric G-proteins with y, a, B subunits and GDP attached to the a subunit during inactive state

• different effector proteins as well

What is the general process for all G-protein linked receptors?

1. hydrophilic ligand binds to extracellular side of receptor and causes conformational change to receptor on the cytoplasmic side

2. this change causes receptor to bind with G-protein, which causes GDP to be exchanged with GTP which activates the G-protein

3. once activated, the G-protein splits into By and a subunits that can both interact with target proteins in plasma membrane, but we are usually primarily interested in what the a subunit is doing → go and activate effector proteins

4. upon activating the effector protein, the a subunit replaces GTP with GDP and that shuts down the protein → the trimeric G-protein reunite

What effector protein do all G_s coupled protein receptors interact with?

adenylate cyclase

Explain the G_s protein linked receptor pathway

1. signal stimulus binds to the extracellular side of receptor and activates it

2. the activated receptor then activates the trimeric G_s protein

3. the a subunit of the G_s protein goes to adenylyl cyclase and activates it, which deactivates the G_s 

4. when adenylyl cyclase is activated, it catalyzes formation of cyclic AMP (cAMP)

5. cAMP is a 2nd messenger, which goes and activates Protein Kinase A (PKA)

   1. Phosphodiesterase quickly degrades cAMP

6. PKA moves into the nucleus and phosphorylates specific gene regulatory proteins

   1. PKA can also phosphorylate proteins in cytosol

7. when phosphorylated they go and stimulate the transcription of a whole set of target genes

Explain G_Q protein linked receptor pathway

1. ligand binds to extracellular end of receptor which causes intracellular part to bind to G_Q trimeric protein and activate it, causing a subunit to go and activate Phospholipase C (PLC)

2. the activated PLC cleaves PIP₂ into two different second messengers: IP₃ and DAG 

3. IP₃ binds to a ligand gated ion channel on the smooth ER, which opens a gate to allow Ca²⁺ to leave smooth ER

4. DAG goes to Protein Kinase C (PKC) and removes the inhibitory protein attached to it

   1. DAG is hydrophobic so it remains embedded in the intracellular side of the membrane

5. the Ca²⁺ from IP₃ subpathway also goes to PKC and helps it go do other stuff

6. basically DAG and IP₃ together maximize what PKC does

What does the G_i protein linked receptor pathway do?

• it inhibits adenylyl cyclase, in turn inhibiting production of cAMP, inhibiting activation of PKA, and inhibiting activation of gene regulatory proteins

What does G_t protein linked receptor pathway do?

• stimulates cGMP phosphodiesterase production

What degrades cAMP? Why is fast cAMP degradation necessary? What happens if cAMP is not degraded?

• Phosphodiesterase (PDE) degrades cAMP

• it is important to shut down cAMP quickly to maintain sensitivity of the cell to the extracellular signal molecules

Give an example of a natural phosphodiesterase inhibitor and explain how it works

• Caffeine is a natural inhibitor of PDE that breaks down cAMP

• it allows cAMP to continue staying in the cell, causing PKA to continue being activated

• in neuronal cells, the PKA continuing being activated leads to improved synaptic transmission and increased neuronal activity → which is why caffeine is a stimulant 

What are the two ways in which G protein pathways are regulated? (at least the ones we studied)

• the G protein a subunit is self-regulating in the sense that it turns off (replaces GTP with GDP) after activating effector protein

• Phosphodiesterase breaks down the cyclic nucleotides (cAMP or cGMP) to preserve sensitivity of cell receptor to signal

Explain how ion channel-linked receptors work

1. a ligand binds to ion channel protein gate on receptor on extracellular side 

2. this causes a conformational change in the shape of the gate, making it go from closed to open

3. ions (Na+, K+, Ca2+, Cl-, etc) can be let out or in depending on concentration gradient

How do ion channel-linked receptors convert signals?

• they convert a chemical signal (in the form of a hydrophilic ligand) into an electrical signal because ions bring a charge with them whether they are leaving or entering the cell, and therefore cause a change in voltage across the plasma membrane of that cell

• this is especially important in the nervous system

How do enzyme linked receptors work? Give the name of an example

• ligand binds to receptor, causes conformational change in the enzyme, triggering activity

• ex) receptor tyrosine kinases (RTK)

What are receptor tyrosine kinases (RTKs)? Give a specific example

• basically RTKs cause assembly of an intracellular signaling complex on the intracellular tail of the receptor (from trans-autophosphorylation after dimerization of receptors) 

Explain how the epidermal growth factor receptor pathway works

1. 1 epidermal growth factor (EGF) binds to extracellular end of 1 epidermal growth factor receptor (EGFR) 

2. this causes dimerization of the EGFR 

   1. basically another EGF must bind to another EGFR and that causes two of them to bind to each other (dimerize)

3. this dimerization causes enzymatic activity that causes trans-autophosphorylation basically all the tyrosine residues on the EGFRs get autophosphorylated

4. the phosphorylated tyrosine residues activate downstream scaffolding cytoplasmic proteins

   1. the tyrosine on the EGFR are called receptor tyrosine kinase (RTK)

   2. scaffolding proteins are aka adaptor proteins

5. these proteins build a bridge between the (RTK) and the Ras protein, activating it

   1. unactivated, the Ras protein has a GDP but upon activation it gets a GTP (Ras GDP → Ras GTP)

   2. the Ras protein is bound to plasma membrane on cytoplasmic side by a lipid tail

6. when activated, Ras protein activates a phosphorylation cascade

   1. phosphorylates MAP-kinase-kinase-kinase. which phosphorylates MAP-kinase-kinase, which phosphorylates MAP-kinase, which phosphorylates several other target proteins

   2. these other target proteins can affect cell metabolic activities or activate transcription factors etc.

7. eventually causes cell growth in case of EGF

How similar are all growth factor receptor pathways?

• they have different signaling ligands and different ligand-specific receptors, but the main process is the same

• the pathways all activate the Ras-GTP

• once Ras-GTP is activated it will cause proliferation of the cell

What is the connection between the Ras gene and cancer?

• ~30% of human cancers involve mutations of the Ras gene that cause it to be constitutively activated

  • basically a mutation of the gene causes Ras proteins to always be bound to GTP (turned on) therefore constantly stimulating cell proliferation

  • uncontrolled cell proliferation is cancer

• Ras protein is a monomeric GTP protein which dephosphorylates the GTP to GDP and turns itself off under normal conditions