Ch1 Fundamentals

Homeostasis: Hold at a steady state.

Negative feedback mechanisms are crucial in regulating homeostasis

Feedback Loops:

Negative Feedback: (more common)

The system is composed of four parts, sensor, controlled variable, effector, and controller.

The controller has a set point and the controller has a comparator which compares with the sensor input and it will send an error signal (within the controller) and actuating signal (exits the controller) to effectors.

e.g., Keep warm in winter:

sensor is the thermometer, the controlled variable is the temperature, the controller is the thermostat, the effector is the furnace/heater

if the room temperature are no smaller than the set point, the error signal is 0/+ and the actuating signal will not be sent

e.g., body temperature, mood, plasma concentration of (H2O, H+, Ca2+, Glucose)

e.g., body temperature

controlled variable is the body temperature

sensor is the thermoreceptors

controller is the hypothalamus

effectors are the skeletal muscles, skin arterioles (thin blood vessel on skin, which dilation would cool down body temperature), sweat glands, etc..

Positive Feedback:

The system is composed of four parts, sensor, output variable, effector, and amplifier.

no controlled variable or set point

properties:

plateau, maximum value of output of effector

threshold, level of output variable at which point system rapidly drives towards plateau

e.g., Action potential (V-gated Na channels),

e.g., labor and childbirth

output variable: pressure in cervis and uterine wall

sensor: pressure sensitive sensory neurons in cervix and uterine wall

amplifier: hypothalamus/pituitary

actuating signal: oxytocin

effector: uterine smooth muscle

plateau: the maximum force that the uterine smooth muscle can generate

Transport

three primarily focused factors that drives movements

pressure (heart pumping blood), concentration (diffusion), electrical charge (v-gated channels)

transport across semipermeable membrane

w/o protein: oxygen gas, steroid hormones, water (in small amount)

w/ protein: ions, glucose, water (in large amount)

Water diffusion aka osmosis, isotonic is ok, hypotonic is more solute in cell and the cell will swollen, hypertonic is less solute in the cell and the cell will shrink

factors for ion transport

concentration gradient

charge gradient

For a real cell:

K concentration is higher inside the cell and Na concentration is lower inside the cell

K is more closer to equilibrium

Ways of transports:

Passive
- Simple Diffusion
- Diffusion via channel
  Channel allow diffusion through membrane
  1. ion channels
  1. aquaporins
- uniporter carrier protein
  allow passive movement

Active
- Primary active transport
  e.g., Na/K ATPase (3Na out, 2K in) took 30% of all energy
- Secondary active transport
  e.g., SGLT1 and SGLT2 are Na/glucose co-transporter (Na down the gradient, glucose up the gradient)

endocytosis
engulfing extracellular substances
internalization of transmembrane proteins

exocytosis
Secretion of proteins or other messengers
trafficking of transmembrane proteins to membrane

Cell-to-cell communication

The chemical messenger/ligand/first messenger binds to a specific receptor molecule

Ligand type:

Lipid soluble messager — binds to receptors in cytoplasm or nucleus

Water soluble messager — binds to the receptors on the cell membrane. e.g., ionotropic receptors (nAchR)

GCPRs G-Protein Coupled Receptors

Receptor associated with heterotrimeric G protein (alpha, beta, gamma)

Ligand binding causes alpha subunit to bind GTP instead of GDP

GTP binding causes the alpha subunit to dissociate from beta, gamma subunit

The alpha subunit interacts with and activates a transmemebrane enzyme or ion channel

The alpha subunit has intrinsic GTPase activity, turning itself off by catalyzing cleavage of the third P in GTP

Subunits reassoicate with each other and receptor

e.g., oxytocin binds with GPRC

e.g.

G alpha subunit activates adenylyl cyclase

Adenylyl cyclase catalyzes production of cAMP from ATP

cAMP binding activates cAMP- dependent protein kinase (also called Protein Kinase A (PKA))

Key notes:

Importance of second messengers in signaling pathways

Amplification of a signal

Key role of kinases in many signaling pathways

Hormone: a secreted molecule that travels through the blood to target cell(s), exerts some effect based on interaction with receptor

Some hormones can acts as NeruoTransmitters

Endocrine System

Are one of the two main physiological control system. (with nervous system)

Roles in widely varying physiological function such as homeostatic regulation of ions, energy availability, and coordinated changes such as growth and development.

Comparisons between Endocrine and Nervous System

NS are targeted at one cell via synapse, fast, shorter duration

ES are by the hormone that are secreted by endocrine gland, more cells, slower, longer duration

Hypothalamus (with pituitary gland below it)

Hypothalamus have neurosecretory cells whose axons release hormones into capillaries in posterior pituitary, and neurosecretory cells whose axons release hormones into portal system that transports blood a short distance to anterior pituitary.

A Stress Response pathway

Stress (such as psychosocial stress, temperature, fasting, exercise, and anything that are a threats to homeostasis)

$\rightarrow$ hypothalamus release Corticotropin Releasing Hormone (CRH)

$\rightarrow$ anterior pituitary release AdrenoCorticoTropic Hormone (ACTH)

$\rightarrow$ adrenal cortex release cortisol

$\rightarrow$ most tissues response to cortisol

Adrenal gland releases several hormones

Inner most section: Medulla

Releases epinephrine and norepinephrine

Outer section: cortex

Inner: Zona Reticularis

releases androgens and small amount of cortisol

Mid: Zona fasciculata

releases cortisol and small amount of androgens

Outer: Zona glomerulosa

release aldosterone

CRH, ACTH are water soluble and Cortisol are lipid soluble

Cortisol

Stimulation of liver cell uptake of amino acids and conversion to glucose.

Stimulation of triglyceride breakdown in adipocytes.

Inhibition of inflammation.

Inhibition of nonessential functions (e.g. growth and reproduction).

Inhibits CRH and ACTH release and thus inhibit cortisol release

Insulin Pathway

Sensor: Beta islet cells in pancreas

Controller: Beta islet cells in pancreas

Actuating signal: Insulin

Effectors: Skeletal muscle, adipocytes, liver cells

Controlled Variable: blood plasma glucose level

Beta islet cells has Glut2 transmembrane protein (glucose transporter protein)

Glucose would be converted into ATP

ATP binds to ATP-sensitive K+ channel ( $\text K_{\text{ATP}}$ )

K+ stop flowing out of the channel

This cause an increase in cell potential

This cause V-gated Ca2+ channels to open

Ca2+ flows into the cell (positive feedback loop in increasing cell potential)

Exocytosis release insulin

Insulin would activate insulin receptor (transmembrane, tyrosine kinase), which would stimulate Glut4 exocytosis and thus increase Glut4 intake. (skeletal muscle)

Insulin would activate insulin receptor, which initiate production of glycogen (from glucose, glycogenesis, which glucose if transported into the cell via Glut2) (liver cell)

Glucagon pathway

Sensor: Alpha islet cells in pancreas

Controller: Alpha islet cells in pancreas

Actuating signal: Glucagon

Effectors: Liver cells

Controlled Variable: blood plasma glucose level

Glucagon binds to glucagon receptor (GPCR), increase cAMP, produce glucose from glycogen (glycogenolysis), glucose flows out of the cell via Glut2.

Diabetes Mellitus

Plasma glucose level are very high

Type 1, problem with beta islet cells, that not enough of insulin produced (might be because of auto-immune diseases)

Type 2, insulin insensitivity in skeletal muscle, adipocytes, and or liver cells

Ca2+ is important

Insulin release

Parathyroid hormone signaling

Neuronal signaling

Muscle contraction

Ca2+ regulations

includes

Parathyroid glands

Bones

Kidneys

GI tract

Negative feedback loop

Controlled variable: plasma levels of Ca2+

Sensor: Parathyroid gland cells via CaSR (Calcium Sensing Receptor)

Controller: Parathyroid gland

Actuating signal: PTH

Effectors:

Bone
Osteoclast break down calcified extracellular matrix in bone tissue, which releases Ca2+

Kidney epithelial cells
increase Ca2+ reabsorption

Kidney endocrine cells
release 1,25 dihydroxy vitamin D (lipid soluble), binds to Vitamin D Receptor (VDR) (in intestine) and it enter the nucleus, and turns up TRPV6 transcription, and TRPV6 would merge with the cell membrane and it is a Ca2+ channel that intakes Ca2+

Parathyroid glands:

Located near the throat

Express a transmembrane receptor called Calcium Sensing Receptor (CaSR)

CaSR is GPCR

Ca2+ binds to CaSR and initiates a pathway that inhibit ParaThyroid Hormone (PTH) release

PTH is hydrophilic hormone that binds to GPCR

PTH pathway

Adenylyl Cyclase / cAMP / ProteinKinaseA pathway

Phospholipase C Pathway
1. Activates Phospholipase C
1. Activate IP3 (release Ca2+ from ER and ), DAG (activate Protein Kinease C), Ca2+ (released by Ca2+)