Movement = Driving force/resistance

"Movement is directly proportional to driving force and inversely proportional to resistance."

1. passive/non-carrier mediated - simple diffusion through lipid bilayer, through pores, through gated channels

2. passive/carrier mediated - facilitated diffusion

3. active - primary (ATP hydrolysis, energy release from redox reactions) and secodary (coupled transport, co-transport, exchangers)

Pores - proteins located in membranes that are always open. flux through pores depends on concentration gradient and permeability (size and # of pores/unit surface area)

Gated channels - pores with a gate. if it's closed, nothing goes through. if it's open, it acts like a pore

Carriers - protein that undergoes conformational change when selected molecule binds and dissociates

Primary active transport: solute movemnt against an electrochemical gradient. Carrier-mediated, requires enerrgy that can be provided by:

ATP hydrolysis (Na/K pump)

Direct link to a primary metabolic reaction (redox rxn that occurs in intermitochondrial membrane of electron transport chain)

3 Na+ out

2 K+ in

The pump binds ATP and 3 intracellular Na ions.

ATP is hydroluzed, which phosphorylates the pump and releases ADP

A conformaitonal change of the pump exposes Na to the outside. The pump also now has a low affinity for Na, so it releases it.

The pump now has a high affinity for K, so it binds 2 extracellular K, which causes dephosphorylation of the pump, reverting it to it's original conformation and exposing the K (which the pump now has a low affinity for) to the inside of the cell

K is released, ATP binds, and the process starts over

F0 - domain which is integral in the membrane

F1 - peripheral

Co-Transport/symport: If solute moves in teh same direction across the cell membrane

ex: Na+, glucose cotransport in small intestine

Exchange/antiport: if solute moves in the opposite direction across cell membrane (Ca2+/Na+ exchange)

tight: distal convoluted tubule and collecting duct of kidney

leaky: proximal tubule of kidney

nerve and muscle

excitability is the ability of cells to respond to stimuli by a change in membrane potential or generation of action potential

conductivity is a property of a cell which enables the effect of a stimulus to be transferred from one part of a neuron to another, an excitation of one part of a neuron is conducted to all other parts

chemical messengers

signal transduction

intrinsic regulation

extrinsic regulation

Direct: the ions and small molecules pass directly through connexons (gap junctions) from the cytoplasm of one cell to the cytoplasm of another (cardiac muscle). The tissue functions as a single unit. Much faster.

Indirect: a ligand secreted from one cell binds to a receptor on itself or another cell

paracrine - messenger secreted into ECF and diffuses and binds to a receptor on a neighboring cell

Autocrine - messenger secreted into ECF and binds to a receptor on itself

Neurotransmitter - also paracrine, are secreted from neurons, cross the synaptic cleft and bind to a receptor on the postsynaptic cell

Hormones - are secreted into the blood and transport to the target cell where they bind to a receptor

amino acids - amine group, carboxyl grou, R groups

Amines

Steroids - 3 six-carbon rings bound to a 5-carbond ring

proteins

eicosanoids

glutamate - excitatory

aspartate - excitatory

glycine - inhibitory

GABA - inhibitory

Catecholamines (derived from tyrosine):

epinephrine (from adrenal medulla) and norepinephrine (CNS and PNS neurotransmitter AND hormone - from adrenal medulla)

Dopamine - CNS neurotransmitter

Thyroid hormones (T3 & T4)

Serotonin - CNS neurotransmitter from tryptophan

Histamine - paracrine derived from histadine

Glucocorticoids - cortisol

Mineralcorticoids - aldosterone

adrogens - testosterone

estrogens - estradiol

progestins - progesterones

Receptors show specificity for the messenger

Receptor-messenger binding is brief and reversible

A single messenger can bind to more than one receptor

A target cell may have receptors for more than one type of messenger

messenger concentration

number of receptors on target cell

affinity of receptor for messenger (strength of binding)

agonists: are exogenous compounds that bind to a receptor and cause normal biological function

Anatgonists: exogenous compounds that bind to a receptor and block its function

lipophilic - can cross lipid bilayer and bind to intracellular receptors

steroid hormones bind to receptors in cytoplasm

thyroid hormones bind to receptors in nucleus

lipophobic - cannot cross lipid bilayer and thus bind to membrane receptors

proteins - amino acids - amines (except for thyroid hormones)

hormone binds to receptor

receptor-hormone complex bind to DNA a beginning of specific gene. 

Hormone acts as transcription factor to cause gene exporession and results in protein synthesis

new protein regulates cell activity

ligand binds

alpha subunit of the g-protein dissociates and binds to adenylate cyclase

ATP is converted to cAMP

cAMP activates protein kinase A, which phosphorylates a protein to cause a response in the cell

alpha

beta

gamma

beta and gamma act as a dimer

epinephrine works on a g-protein system.

phosphodiesterase convers cAMP to AMP to end the cycle and the action of the kinase.

Coffee inhibits phosphodiesterase and thus allows the action of epinephrine to keep working without being cleared from the cell.

ligand binds, alpha subunit dissociates and activates phospholipase C

PIP2 is convered to IP3 on DAG

IP3 opens ER Ca2+ channels to allow Ca2+ out of ER

CA2+ binds to calmoduline, which activates protein kinase, which phosphorylates the protein, which causes a response in the cell

receptor is also enzyme

ligand binds to receptor , causing conformational change

conformational change activates tyrosine kinase

tyrosine kinase activates intracellular protein

phosphorylated protein brings about target cell response

Channel-linked

enzyme-linked

g-protein

one messenger binds to one receptor. several G proteins are activated. Each G protein activates an adenylate cyclase. Each adenylate cyclase generates hundreds of cAMPs. each cAMP activats a protein kinase A. each protein kinase A phosphorylates hundreds of proteins.

Amplification occurs at adenylate cyclase and protein kinase A

endocrine - releases hormones into the blood to be transported throughout the body

nervous system - transmit electrical signals along the axon which triggers a chemical signal across a synapse

primary: major fxn is to secrete hormones.

hypothalamus, pituitary, pineal gland, thyroid, parathyroid, thymus, adrenal gland, pancreas, gonads

secondary: has another major fxn but also secretes hormones.

heart, liver, stomach, small intestine, kidney, skin

the hypothalamus synthesizes and releases oxytocin and ADH in secretory vesicles which are transported to neural endings in the posterior pituitary. the posterior pituitary releases the oxytocin and ADH after receiving a signla from another neuron. They are then released through exocytosis.

ADH = vasopressin = antidiuretic hormone.

The hypothalamus produces hormones that are transported through the H-P portal system to the anterior pituitary.

These hormones signal the anterior pituitary to release other hormones that it has synthesized.

prolactin

prolactin

thryoid stimulating hormone

adrenocorticotropic hormone

growth hormone

growth hormone

follicle stimulating hormone and luteinizing hormone

Thyroid axis - thyroid releasing hormone secreted from hypothalamus. causes ant pituitary to release thyroid stimulating hormone. acts on thyroid gland and releases thyroid hormone.

Adrenal Axis - corticotropin releasing hormone secreted from hypothalamus. causes anterior pituitary to release adrenocorticotropin hormone. acts on the adrenal cortex and releases cortisol.

Liver axis - growth hormone releasing hormone and growht hormone inhibiting hormone are released from hypothalamus. causes ant pituitary to release growth hormone. acts on liver and releases insulin like growth factors.

Gonad axis - gonadotropin releasing hormone released from hypothalamus. causes ant pituitary to relase leutenizing hormone and follicle stimulating hormone. acts on the gonads - males release androgens, females release estrogens and progesterone

antagonistic - 2 hormones that have opposite effects. parathyroid hormone increases blood calcium levels and calcitonin decreases them.

additive - 2 hormones have the same effect and the net effect equals the sum of the individual effects.

synergistic - 2 hormones have the same effect and the net effect is greater than the individual effects.

permissive - one hormone is needed for another hormone to exert its actions. such as when epinephrine caues bronchodilation.

coloumb's law

F=K(qa.qb/r^2)

F= force between two particles

qa = charge of particle a

qb = charge of particle b

r = separation between particles

K = constant

Ohm's Law

I=V/R

I = currrent

V = voltage

R = Resistance

current

voltage

resistance

To increase current, you must either increase voltage or decrease resistance

current flow for cations will be:

negative when membrane pot is below equilibrium potential

positive when membrane pot is above equilibrium pot

1. Gibbs-Donnan potential - determined by fixed, negative charges (proteins, AMP/ADP/ATP)

2. Net Diffusion potential (Ediff) - MOST SIGNIFICANT

3. Electromagnetic ion pump potential (Ep) - LEAST SIGNIFICANT

Delayed outward rectifying: repolarize membrane. Slow to open and close.

Transient outward rectifying: early repolarization in myocyte APs. Open and close quickly

Inward rectifying: stabilize Vm. Allow one-way movement of K+ into cell to oppose the electrochemical gradeitn diffusion of K+ out of cell.

function to stabilize resting membrane potential at Vm=-90. Allows K+ to flow in to counterbalance other channels' outward flow. 

Mg2+ ions block K+ from flowing out of cell through these channels, but allows K+ to flow in.

RMP

Stimulus - if threshold, voltage-gated Na+ channels open and depolarize membrane

Kv1.1 channels (delayed outward rectifying) and repolarize membrane

K+ close slowly, resulting in hyperpolarization of membrane

Na+ channels have an activation gate and an inactivation gate. When at RMP, the activation gate is closed and inactivation gate is open. When threshold is reach, the activation gate opens, allowing for inward flow of Na_. Almost simulataneously,, the inactivation gates reset to their original orientations (absolute refractory period).

K+ channels only have an activation gate, which is either open or closed.

RMP = -90mV

Threshold = -70mV

Depolarization - carried by Na+ current (INa channels)

Repolarization - K+ current as a result of opening of Kv1.1 voltage-gated channels

takes about 15-20 msec

Phase 4 - RMP. Kept at -90mV by inward rectifying voltage-gated K+ channels (Kir), which stabilize the membrane by providing an inward rectifying flow of K+ (IKir) to counterbalance outward flow of K+ due to electrochemical gradient.

Phase 0 - upstroke (depolarization) carried by Na+ current (INa)

Phase 1 - early repolarization. results from a transient outward K+ current (Ito) through A-type rectifying channels (Kv1.4) which open as the membrane potential becomes more positive due to inactivation Na_ channels and close shortly thereafter.

Phase 2 - plateau. results from balance between inward Ca2+ and outward K+ current. Ca 2+ is carried through long-lasting L-type voltage-gaed channels that open slowly at about -40mV during Phase 0. K+ current is the result of the dying out of Ito and the opening of delayed rectifying K+ channels Kv1.1.

Phase 3 - Final repolarization. Carried by K+ through Kv1.1 channels as Ca2+ channels close, resulting in a strong outward IKv1.1.

Phase 4 - Slow diastolic depolarization. AKA Pacemaker potential. Happens spontaneously. Made up of 3 currents:

- Funny current (If) - carried by Na+ through nucleotide channels which open when the membrane potential drops below -50mV during repolarization. This is predominating current.

- Transient Ca2+ current (ICaT) - carried through T-type Ca2+ channels, which open when Vm reaches -55mV during depolarization.

- Delayed rectifier K+ current (Kv1.1) - outward current that opposes the two inward currents.

Phase 0 - upstroke (depolarization). After threshold is reached, carried by Ca2+ L-type channels (ICaL)

Phase 3 - Repolarization. Carried by K+ delayed rectifier current (IKv1.1)

Depolarization: Ca2+ channels open.

Repolarization: IKv1.1

Smooth muscle doesn't have Na+ channels so it uses Ca2+ channels and therefore it happens more slowly

Absolute: time during which a second AP cannot occur at the location of the first on eunder any circumstances due to Na+ channel inactivation.

Relative: Period during which a second AP can occurs but it requires a much stronger than usual stimulus. Due to Kv1.1 channels being open, whcih tends to hyperpolarize the membrane, so it requires a lot of Na+ to counteract the hyperpolarization. Begins about when the membrane reaches threshold during repolarization.

G-Actin monomers combine into an F-actin filament. Each G-Actin has a myosin binding site.

In the resting state, the myosin head is at a 90 deg angle to the actin, but it is not bound. the mysoin head has ADP and Pi bound. Tropomyosin is blocking the myosin binding sites on actin.

Ca2+ binds to troponin, which causes a conformational change, which pulls tropomyosin off of actin and epxoses the myosin binding sites. the myosin head binds to the actin. still at 90 deg angle.

The ADP and Pi are released, causing the powerstroke where the myosin head contracts to a 45 deg angle and moves the actin filament, shortening the sarcomere.

ATP binds to myosin head, myosin releases from actin.

ATP is hydrolyzed and myosin head resets to 90 deg angle.

The sequence of events that links the AP to contraction (and to the cross-bridge cycle).

During an AP, Ca2+ is released from the sarcoplasmic reticulum into the cytoplasm where it can bind to troponin and pull tropomyosin off actin to allow myosin to bind.

Skeletal: mechanical coupling. channels connected to the T-tubules. membrane depolarization opens the L-type Ca2+ channel and causes the Ca release channel to open.

Cardiac: Ca induced Ca release (CICR) - Ca enters the cell via L-type Ca channels, whcih activates the Ca release channels. No physical connection between T tubule and channel

isometric - if a muscle is anchored at both ends and stimulated it will generate force without chanign length (force is less than load) - like trying to push the wall back

isotonic - if a muscle is anchored at one end and a weight is attached to the other, muscle stimulation results in force generation and muscle shortening (force is greater than load) - like lifting a marker

latent period - events of EC coupling to the point of Ca release from SR

contraction phase - ca binds to troponin and cross-bridge cycling rate is increasing. (upstroke)

relaxation phase - ca is being pumped back into SR and CB cycling rate is decreasing

summation - with each successive stimulus, more ca is released and the muscle contracts more than it would have because it has not fully relaxed by the time the next stimulus comes.

tetanus - myosin binding sites are saturated and muscle does not have time to relax between stimuli so it remains at full contraction.

Length constant decreases with increased cytoplasmic resistance (indirectly porportional)

Length constant increases with increase in membrane resistance (directly proportional). the more impermeable the membrane is to chare, the greater resistance it has.

electrical: plasma membranes of adjacent cells are linked together by gap junctions such that when an electrical signal is generated in one cells, it is directly trasnfered to the adjacent cell. Fast communication.

Chemical: one neuron secretes a neurotransmitter into the ECF in response to an AP arriving at its axon terminal. the neurotransmitter then binds to receptors on the plasma membrane of a second cell, triggering an electrical signal that may or may not initiate an AP.

presynaptic neuron

postsynaptic neuron

synaptic cleft

current flow via gap junctions. gap junctions are areas of the membrane containing connexon proteins that form channels linking the cytoplasm of two adjacent cells

signal jumps at nodes of ranvier

Equilibrium potential = the point at which the electrical gradient and chemical gradients for a specific ion are equal and the net movement is zero.

Calculated with Nernst Equaiton:

Ex= (-RT/zF)ln(Xi/Xo)

Water can cross a lipid bilayer but only does so very slowly. For water to cross easily, it needs a pore that it can go through called an aquaporin.

2 types of aquaporins:

AQP1: are always present in a cell membrane. used for high volume water transport, such as in RBCs and renal proximal convoluted tubules.

AQP2: are inserted by hormonal control as needed. For instance Antidiuretic hormone inserts these aquaporins regularly. Lasix facilitate the function of AQP2 in CHF pts. When someone is on lasix and lots of AQP2 are functioning, they have to pee a lot.

Gibbs-Donnan Equilibrium: fixed negative charges in cytoplasm lead to ionic movement across membranes. Results in chemical, electrical, and osmotic equilibrium.

Osmotic work is done to counteract the excess pressure of H2O entering a cell from Donnan forces. It is accomplished by active transport of Na/K ATPase which keeps an equal number of neg and pos ions on either side of the membrane and thus keeps excess water from entering the cell to equalize the solute concentration inside the cell, which would lyse the cell.

Epithelial cells separate interstitial fluid from lumen

2 membranes:

1. Apical, AKA:

a. brush border

b. mucosal membrane

c. luminal membrane

Faces toward lumen

2. basolateral membrane. AKA serosal or peritubular membrane. Faces toward interstitium

Transcellular: substances cross the cell by sequentially passing through the apical and basolateral membranes

Paracellular: substaces bypass the cell and cross throguh tight junctions

fast and slow

Fast - receptor and channel are the same protein

Slow - receptor and channel are different proteins coupled by a G protein

1. Affects the resting membrane potential

2. Creates the fixed negative charge in a cell because big, negatively charged ions are unable to get out of a cell.

3. Contributes to ion movement into and out of a cell

K: around +60

Na: around -90

RMP: -90

Indirect effect of Na/K ATPase (80% contribution)

Gibbs-Donnan potential (14%)

Direct effect of Na/K ATPase (6%)

Em=Ediff+Ep

Ediff = diffusion potential (calculated by chord conductance equation) - combined contributions of Gibbs-Donnan effect and charge separation

Ep = electrogenic ion pump potneital (-4mV, unless otherwise given)

a = Sodium

b = potassium

2 neurotoxins:

TTX (tetrodotoxin)

STX (Saxitoxin)

and 2 local anesthetics:

Lidocaine

Tetracaine

L-type:

Long lasting

high threshold (>-30mV)

blocked by DHP's

Located in heart, skeletal muscle, neurons, smooth muscle, uterus, and neuroendocrine cells

Function to link depolarization to intracellular Ca signaling

T-type

Transient

low threshold (<-30mV)

not easily blocked by DHPs

Found in SA node and brain neurons

Function by repetitive firing of APs in heart and neurons

Inotropic - form transmembrane ion channels that open and allow ions to flow upon binding of a ligand

Electrical - form voltage-gated channels where electrical gradients form allowing ions to move between cells.

Metabotropic - are indirectly linked with ion channels, but do not form them. When the ligand binds, the synapse releases signals which then leads to the opening of an ion channel

1. Presynaptic cell contains vesicles of acetylcholine. When it is released, it binds to the nicotinic acetylcholine receptors on the postsynaptic cell.

2. When Acetylcholine binds, it increases permeability of that membrane for cations, which allows Na and K to move and results in depolarization of the membrane, first by the opening of ligand-gated Na/K channels (graded response) and then throguh the opening of voltage-gated Na channels once threshold is reached.

3. The AP travels across the sarcolemma and down the t-tubules and triggers the release of Ca2+ from the sarcoplasmic reticulum and triggers muscle contraction through cross-bridge cycling

EPSP - Excitatory postsynaptic potential. the electrical impulse that causes depolarization down the axon hillock during a synaptic transmission. makes it  easier for an AP to occur. Na moves in, Cl- moves out.

IPSP - inhibitory postsynaptic potential. the electrical potential results in hyperpolarization of the cell due to Na coming back in the cell. keeps another AP from occuring. Na+ moves out, Cl- moves in.

Both are graded potentials

Temporal - several impulses from one neuron over time.

Spatial - multiple impulses from several neurons occuring at the same time.

Whether or not threshold is reached is dependent on these summations.

skeletal: electrical stimulation by somatic motor neurons

cardiac: electrical stimulation by autorhythmic cells through gap junctions

smooth: neuron stimulus or gap junctions

contractile component: sarcomeres

series elastic component: cytoskeletal material connecting myofibrils to ends of fibers, connective tissue that anchors fibers to tendons, and tendons that anchor muscle to bones... all generate passive force when stretched and act like a rubber band.

active - optimum length of 100-120% for generating maximum active force. any length overlap or below 100% when contracting decreases force. any length greater than 120% decreases force.

passive - force generation increases as the series elastic components are stretched past their resting state.

total force - maximum total force is generated when active and passive forces are generated from the optimum length.

threshold - minimum stimulus required to get a measurable twitch

maximal stimulus - minimum stimulus that results in recruitment of all motor units for that muscle, generating the most force of contraction possible for that muscle

isotonic twitch has 3 phases:

latent - muscle is developing tension without changing length

plateau - muscle is shortening at constant tension

relaxation - muscle tension decreases to zero

the larger the load, the longer the latent period and relaxation periods, but the shorter the plateau period. once the load force exceeds the muscle force, it is isometric contraction (no plateau because no change in muscle length)

the smaller the load, the higher the velocity.

velocity is highest with no weight

when load > power of contraction = isometric contraction = no velocity

the shorter the muscle fiber, the smaller the load to reach isometric contraction, so larger muscles can maintain a higher velocity for longer