Important class of signaling complexes; coupling receptors interact with G protein

• membrane receptor is activated by an extracellular signal
• G protein transfers the extracellular signal into the intracellular compartment by interacting with a target
• target enzyme produces an intracellular "second" messenger

MEMBRANE RECEPTOR à

G PROTEIN à

ADENYLYL CYCLASE

RECEPTOR

• in the plasma membrane
• over 1000 G protein coupled receptors
• integral membrane protein with 7 alpha helical regions spanning the membrane (heptahelical)
• amino terminus extra-cellular
• carboxy terminus intracellular

G PROTEIN

• on the intracellular face of the plasma membrane
• (heterotrimeric) consists of 3 subunits labeled alpha (α), beta (β), and gamma (γ)
• interacts with receptor occupied by a signaling molecule
• when activated receptor activates with an effector element

EFFECTOR ELEMENT (enzyme or ion channel)

• Enzyme --> produces an intracellular "second" messenger ex) adenlyl cylase is an integral membrane protein

• ion channel --> controls movement of ions across the plasma membrane

The funtion of the following G proteins:

G_s

G_i

G_olf

G_t

G_s - stimulatory G protein that stimulated adenylyl cyclase

G_i - inhibitory G protein that inhibits adenylyl cyclase

G_olf - olfactory G protein

G_t - transduction, G protein involved in vision

Alpha α

Beta β

Gamma γ

• an activated receptor interacts with the G protein
• GTP replaces GDP on the α subunit
• the G protein dissociates into α-GTP and a βγ dimer
• the G protein is now "on"
• activated G protein subunits interact with their target (enzyme or ion channels)

• produces cAMP from ATP
• the enzyme is modulated (positive and negative) from by different G proteins
• intracellular cAMP levels go up or down
  • depends on the summation of all signals on that cell

(t/f)

Each cell type expresses a single type of receptor

(T/F)

Each first messenger binds to a single type of receptor

• Activates an enzyme called protein kinase
• Second messenger

• Phosphoylates target proteins (PROTEIN PHOSPHORYLATION)
  • covalent transfer of phosphate group from target proteins
  • post-translational modification

• Reverses phosphorylation of proteins
• these enzymes remove the covalently bound phosphate groups

• amplify faint signal
  • a few "first messenger" molecules
  • many second messenger molecules
• elicit a coordinated response
• each step recruits more molecules

• a signaling cascade if phosphorylation events activates transcription in the nucleus
• another cross of cell signaling complexes involves receptors which can function as kinases

• consists of hormones and the glands
• endocine glands - ductless glands which secrete hormones into the circulation
• regulation results from the function of the endocrine system and the nervous system
  • example: specialized neurosecretory cells secrete hormones
• regulatory system that maintains homeostasis through hoemones

steady state physiological condition

• regulatory chemicals
• produced in an endocrine gland
• secreted into blood and carried to target cells
• extracellular 1st messengers

• respond to hormone by altering their metabolism
• have receptors for specific 1st messengers
• different cell types have different profiles of receptors

You just had a BIG bowl of ice cream...

Your calcitonin levels are: (elavated/lowered)

Your PTH levels are (elevated/lowered)

ELAVATED

LOWERED

You skipped breakfast to rush to class...

Your insulin (peptide hormone that lowers blood glucose levels) levels are (high/low)

Your glucagon (peptide hormone; raises blood glucose levels) levels are (high/low)

LOW

HIGH

• derived from the amino acid tyrosine and tryptophan
• examples of them include?

epinephine

tryoxine

serotonin

Short polymers of amino acids linked by peptide bonds

Examples of polypeptides:

insulin

glucagon

antidiretic hormone

oxytocin

 Protiens that contain oligosaccharide chains (glycans) covalently attached to polypeptide side-chains.

Examples of glycoproteins:

FSH

LH

TSH

• Hormones insoluble in lipids
• Intracellular receptors
• cycling between the cytopoplasmic and nuclear compartments

Examples of Seroids are:

glucocorticosteroids (cortisol)

mineralocorticoids (aldosterone)

androgens (testerone)

• 2 different types of receptor for the same compound
• found in different cells in different tissues
• nicotinic
• muscarinic
• different types of receptors for the same hormone-elicit different responses

In glucose homestasis, insulin and glucagon are located in the pancreas.

Insulin, in beta cells, is a peptide hormone that ______ blood glucose levels

• Protein produced in bone cells
• influences energy metabolism
• affects pancreatic and fat cells
• skeleton affects energy metabolism

• Abnormally high blood glucose concentrations
• damage proteins through covalent modification due to mass action (=not controlled by enzymes)
• damage tissues and organs

• childhood onset
• autoimmune destruction of cells releasing insulin
• inability to produce insulin

TYPE 1 DIABETES

(INSULIN DEPENDENT)

• adult onset (40+)
• recently seen more frequently in children
• failure of the signal transduction system to elicit a response to insulin or inadequate insulin production
• onset related to obesity and heredity

TYPE 2 DIABETES

(INSULIN INDEPENDENT)

Calcium Homeostasis is maintained by:

1. calcitonin - peptide hormone produced in thyroid gland
2. Parathyroid Hormone PTH - peptide hormone produced in the parathyroid gland

What does each do for regulation?

calcitonin --> lowers blood calcium levels

PTH --> raises blood calcium levels

• bone matrix - collagen principle component
• calcium phosphate deposited in bone
• bone is continuously being remodeled

• problem in elderly women
• loss of calcium in the bones
• age-related alteration in bone homeostasis
• can also result from glucocorticoid administration
• estrogens importent in prevention of postmenopausal osteoporosis
• thought to act by opposing the calcium-mobilizing, bone-reabsorbing effect of PTH

Where are androgens produced?

ex) testosterone; support sperm formation; male secondary sex characteristics

Where are estrogens produced?

*stimulate uterine lining growth. development and maintenance of female secondary sex characteristics*

• glycogen broken down, blood glucose increased
• increased blood pressue
• increased breathing rate
• increased metabolic rate
• change in blood flow decreasing digestive kidney activity

• mineralocorticoids
  • retention of sodium and water
  • increased blood volume & blood pressure
• glucocorticoids
  • breakdown of proteins and fats to increase blood glucose
  • supression of the immune system

CNS

CENTRAL NERVOUS SYSTEM

PNS

PERIPHERAL NERVOUS SYSTEM

contains the nucleus and organelles

clusters are called ganglia

• highly branched processes
• recieve incoming information
• carry this information as an eletrical signal to the cell body

• longer processes
• only one per neuron
• carry information to other cells
• vertebrate axons are insulated with myelin sheaths
• myelinated (fast conducting)
• non-myelinated (slow conducting)

• specialized ending of axon
• relays message to target cell by releasing neurotransmitters

• support cells
• from the Greek word for glue

• structural and metabolic support in the mature central nervous system (CNS)
• form tight junctions resulting in the blood-brain barrier

• In CNS
• form myelin sheath hat insulates the axon of vertebrates

• in PNS
• form myelin sheath that insulates the axon of vertebrates

• non-insulated regions along the axon
• salutatory conduction of nerve impulses

Sodium is ________ outside the resting cell and ______ inside.

high

low

Potassium is __________ outside the resting cell and ________ inside.

low

high

• plasma membrane separates two different environments
• internal environment is high in potassium and low in sodium
• internal environment is slightly more negative
• -70mV
• sodium and potassium channels closed

Resting potential

• only triggered in the axon
• this is the nerve impulse
• stereotypical
• voltage gating-opening/closing depends on the membrane potential
• all or nothing response
  • amplitude independent of magnitude or the depolarizing stimulus
• depolarizing reaches the threshold potential -50mV to 55mV
  • sodium channel open. potassium channel closed

Action potential

• hyperpolarization
  • increased negativity in membrane potential
  • more negative than -70mV of resting potential
  • open potassium channel, potassium fuses out leaving a more negative membrane
• depolorization
  • decreased membrane potential
  • open sodium channe, sodium fuses in, more positive ions in the axoplasm so interior is less negative

out

in

• nerve impulse "jumps" down axon
• myelin sheath insulates (formed by schwann cells)
• nodes of ranvier
  • electrical charges "jump" to these exposed (uninsulated) areas

1. aceylcholine
2. biogenic amines
3. amino acids
4. neuropeptides

o   CNS

o   PNS

o   Neuromuscular junction

o   RECEPTOR TYPES

§  Muscarinic receptor

§  Nicotinic receptor

o   Norepinephrine (Noradrenaline)

§  Also a hormone produced by the adrenal medulla

§  Excitatory or inhibitory

o   Dopamine

§  Generally excitatory

o   Serotonin

§  Generally inhibitory

o   GABA   

§  Inhibitory

o   Glycine

§  Inhibitory

o   Glutamate

§  Excitatory

o   Aspartate

§  Excitatory

o   Substance P

§  Excitatory

§  Mediates perception of pain

o   Endorphins

§  Inhibitory

§  Inhibits pain perception

What are the events that trigger the release of neurotransmitters?

Þ     At the presynaptic membrane, the action potential causes an influx of calcium

Þ     Triggers fusion of synaptic vesicles in the presynaptic cell

Þ     Vesicles release neurotransmitter from the presynaptic membrane

Þ     Neurotransmitters will bind to specific receptors

Þ     A small molecule that can bind to a protein

Þ     EXAMPLES:

o   The substrate for an enzyme

o   An allosteric modulator

o   A hormone

o   A neurotransmitter

The opening of a ligand-gated channel requires the binding of a small molecule (first messenger)

Þ     Excitatory postsynaptic potential

Þ     Depolarizing

Þ     Sodium channels open

Þ     Inhibitory postsynaptic potential

Þ     Hyperpolarizing

Þ     Potassium channel open – potassium diffuses out of the cell and leaves the interior of the cell more negative

IPSP

(Inhibitory Postsynaptic Potential)

Add together the IPSPs and EPSPs that are impinging on the cell

Sums exceeding the threshold result in an _____________

Sums less than the threshold result in ____ action potential

action potential

no

MAKES THE INSIDE OF A TARGET CELL MORE NEGATIVE:

**SENSORY SYSTEM**

Þ     Stretch receptors stimulated by pressure, touch, stretch, motion, or sound

Þ     Hair cells detect motion

o   Found in human inner ear           

o   Found in lateral line of fish and amphibia

Þ     Nociceptors

Þ     Naked dendrites in the skin epidermis

Þ     Detect heat or cold

THERMORECEPTORS

(TEMPERATURE RECEPTORS)

Þ     Gustatory (taste)

Þ     Olfactory (smell)

CHEMORECEPTORS

Electromagnetic Receptors

§  Simple photoreceptors detecting light

§  Planarium worm

§  Allows worm to orient with respect to light

§  Ommatidia

·         Light detector

·         Facets of the eye

·         Multiple lense

§  Excellent at detecting motion

§  Can detect up to 330 flashes/second

·         Human eye only 50 flashes/second

§  Some can detect UV light

§  Mosaic image

§  Insects, crustacean (crabs, shrimp), some polychaete worms

Þ     Single lens

o   Focus image

Þ     Retina

o   Light detection

o   Photoreceptor cells

LIGHT DETECTING CELLS

Þ     Rods and cones

Þ     Contains discs of membrane with photoreceptor proteins embedded

o   7 alpha helical spans

Þ     Receptor protein (opsin) has a light detecting pigment (retinal) attached

Þ     Retinal is a derivative of vitamin A

Þ     Human retina has approximately 125 million

Þ     Sensitive to light

Þ     Cannot distinguish color

Þ     Distributed around the periphery of the retina

Þ     Black & white night vision

Þ     Visual pigment is rhodopsin

Þ     Coupled via a G protein, called transducin, G_t

Þ     Human retina has approximately 6 million

Þ     Distinguish colors in daylight

Þ     IN THE CENTER OF THE RETINA Fovea

Þ     Primates, including humans – 3 types of cones + rods

Þ     Most other mammals – 2 types of cones (blue and green) + rods

Þ     Marine mammals – 1 type of cone (long wavelengths) + rods

o   Essentially colorblind

LIGHT DETECTION IN THE (LIGHT/DARK)

o   Rod cells are depolarized

o   Sodium channels are open

o   cGMP binds to sodium channel and opens it

o   Neurotransmitter glutamate is released and binds to bipolar cells

o   Rhodopsin is inactive

o   Rod cell membrane is highly permeable to sodium and thus depolarized

o   Neurotransmitter is released which inhibits the firing of the postsynaptic neuron

IN THE DARK

LIGHT DETECTION IN THE (LIGHT/DARK)

o   Activated rhodopsin interacts with G_t (transducin)

o   Activated transducin causes a decrease in intracellular cGMP levels

o   Results in hyperpolarization

o   Neurotransmitter glutamate no longer released to act on bipolar cells

LIGHT

o   Via transducin acts by decreasing cyclic GMP levels

o   Activates a phosphodiesterase to breakdown cGMP

o   Cyclic GMP binds to sodium channel and keeps the channel open in the dark

LIGHT ACTIVATED PATHWAYS!!! =)

Þ     Bundle of fibers

o   Single cell with many nuclei

Þ     Fiber made of myofibrils

Þ     Myofibrils made of myofilaments

FILAMENTS:

o   Thin = _____________

o   Thick = ____________

ACTIN

MYOSIN

Þ     Basic contractile unit

Þ     Delimited by Z lines

**SHORTENS WHEN ACTIN MOVES OVER MYOSIN**

Þ     Calcium exposes the site on actin which interacts with myosin

Þ     ATP hydrolysis by the myosin head (ATPase) allows crossbridge formation with actin (up to 5 times per second)

Þ     Results in thin (actin) filament moving over the thick (myosin) filament

WHAT IS THE ROLE OF CALCIUM IN MUSCLE CONTRACTION??

Þ     Calcium released from the sarcoplasmic reticulum (smooth ER)

Þ     Calcium binds to troponin and alters the interaction of troponin & tropomyosin

Þ     Sarcoplasmic reticulum has active transport for the reuptake of calcium

_____ acts as a fast twitch muscle fiber.

Rapid, powerful contraction.

anaerobic poise (glycolysis)

Creatine/Arginine Phosphate)

Þ     Rapid powerful contraction

Þ     More  sarcoplasmic reticulum (specialized smooth ER) allows rapid control of calcium concentrations

Þ     Anaerobic poise

o   Anaerobic glycolysis

o   ATP

o   Creatine/Arginine phosphate

Þ     Long, repeated contractions without fatigue

Þ     Less sarcoplasmic reticulum so calcium remains in sarcoplasm longer

o   Up to 5 times longer contraction than in fast twitch

Þ     Aerobic tissue

o   Supported through Krebs Cycle and oxidative phosphorylation

o Many mitochondria

o   Rich blood supply

o   High levels of myoglobin (oxygen storage protein)

Þ     Striated

Þ     Action potential in one cardiac cell transmitted to other cardiac cells at intercalated disks

o   Provides direct electrical coupling of cardiac cells

Þ     Cardiac cells have “pacemaker” properties allowing them to generate an action potential without input from the nervous system               

o   Skeletal muscle cannot do this

CARDIAC MUSCLE

Þ     Lacks striation

o   Filaments have a spiral arrangement rather than a linear arrangement within the cell

o   No T-tubule system or well-developed smooth ER

§  Calcium must enter via the plasma membrane during an action potential

·         Small amount reaches the filaments

o   Contractions slow

o   Found in walls of hollow organs, e.g., digestive tract & blood vessels

SMOOTH MUSCLE