Differences btw ECF and ICF

• ECF contains different ions(Na, Cl, Bicaronate) plus nutrients(O2, glucose, Fatty acids, amino acids), carbon dioxide, plus other cellular wastes
• ICF contains large amounts of potassium, magnesium, phosphate ions

Body Water

• 3 liters in blood plasma(ECF)
• 13 in Interstitial fluid (ECF)
• 25 liters in intracellular fluid
• total of 42 liters

Protoplasm

(cytoplasm)

• water (70-85% of cell mass in all except fat cells)
• ions(k, mg, phosphate, sulfate, bicarb, Na, Cl, Ca; for cellular control mechanisms)
• proteins (10-20% of cell mass)(structural and functional proteins)
• lipids(phospholipids and cholesterol) (2% of total cell mass, important component of cell membrane and intracellular membranes) 
• triglycerides make up 95% of cell mass in fat cells
• carbohydrates play a vital role in cell nutrition

Cell Membrane

• lipid bilayer(composed of phospholipids and cholesterol
• membrane proteins-integral proteins and peripheral proteins
• membrane carbohydrates (glycocalyx)-form outermost coat of cell, usually in combo with proteins(glycoproteins) and lipids (glycolipids)

Phosphatidylethanolamine

(phospholipid)

• polar head made up of ethanolamine, and phosphate
• glycerol
• fatty acid tail

Integral Membrane Protein

(Function)

• serve as receptors
• serve as adhesion molecules
• carry out transmembrane movnt of water-soluble substances
• serve as enzymes
• play a role in intracellular signaling

Peripheral Membrane Proteins

(function)

• participate in intracellular signaling
• form a submembranous cytoskeleton

Nuclear Membrane

• double membrane
• space btw nuclear membranes continuous with space inside ER
• nuclear pores serve as transport pathway btw cytoplasm and nuclear interior-specificity controlled by Nuclear Pore Complex(NPC)
• nucleolus lacks limiting membrane
• composed of RNA/proteins

Constitutive Vs Regulated Pathway

• Constitutive: secretion is continuous and unregulated
• Regulated Pathway: secretion is directed by hormonal or neural signal

Golgi Apparatus

(Function)

• further processing of substances formed in ER-major function
• synthesis of carbohydrates (hyaluronic acid and chondroitin sulfate)

Hyaluronic Acid and Chondroitin Sulfate

• major component of proteoglycans-secreted in mucus and glandular secretions
• major component of intracellular interstitial fluid
• principal component of bone and cartilage matrix
• critical role in cell migration and proliferation

Lysosomes

• vesicular organelles dispersed in cytoplasm
• provide intracellular digestive system for: 1) damaged cellular structures, 2) food particles ingested by cell 3) unwanted substances such as bacteria
• 250-750 nm dia, surrounded by lipid bilayer membrane, filled with large number of small granules(5-8nm dia, protein aggregates of different hydrolytic enzymes or hydrolases)

Peroxisomes

• physically similar to lysosomes
• 2 major differences: formed by self replilcation, and contain oxidases instead of hydrolases
• breakdown of long chain fatty acids

Oxidases

• catalyze interaction of O2 with H-ion derived from intracellular chemicals-H2O2 in association with catalase(oxidase enzyme) detoxify chemicals by oxidation (alcohol) 

Pinocytosis

• ingestion of minute particles forming vesicles of ECF and particulate constituents inside cell cytoplasm
• continual process in cell membrane of most cells
• generates small amounts of ATP
• non-specific

Steps of Phagocytosis

• cell membrane receptors bind to surface ligands on the particle
• membrane evaginates outward to surrounding particle-phagocytic vesicle
• cytoplasmic actin/contractile fibrils surround phagocytic vesicle, contract to push vesicle to interior
• contractile proteins pinch off vesicle from cell membrane

Function of Lysosomes

• digestion of pinocytotic/phagocytotic foreign subst
• tissue regression to smaller size
• removal of damaged cells: lysosomes rupture releasing hydrolases
• also contain bactericidal agents: lysozyme(dissolve bacterial membrances), lysoferrin(bindo iron and other subs prior to promoting bacterial growth), and acid at pH 5 (act hydrolases and inactivate bacterial metabolic systems

Mitochondria

• less than 100 to severall 1000 per cell
• oxidative enzymes attached to inner membrane
• inner mitochondria filled with matrix containing large amounts of enzymes required for deriving energy from nutrients
• enzymes in mitochondrial matrix associate with oxidative enzymes->nutrient oxidation->Co2+water +energy in form of atp

Mitochondria

(function)

• site of oxidative energy production
• >95% of cellular ATP production
• serves as reservoir for intracellular Ca2+
• plays central role in apoptosis

Adenosine Triphosphate(ATP)

• adenine, ribose and 3 phosphate radicals
• each high energy phosphate bond has 12000cal energy per mole of ATP
• high energy phosphae bond is labile)can be split readily
• Acetyl-CoA converted to Co2 and H2O to drive formation of 36ATP 

Uses of ATP 

• Membrane Transport (ions and organic substances)
• synthesis of chemical compounds (proteins, phospholipids, cholesterol, purines, pyrimidines)
• mechanical work (muscle contraction)

Intermediate Filaments

• ex vimentin and keratin
• fibrillar in structure
• provide structural support
• tetramer of two coiled dimers (diameter 8-10)

Microtubules

• example is tubulin
• polymers formed from heterodimers of α and β tubulin
• originate from microtubule-organizing center(centrosome)
• provide structural support; form the basis for subcellular motility; cell division
• binds GTP and hydrolyzes to GDP

Thin and Thick Filaments

• thin filaments (actin) are functionally similar to tubulin
• thick filaments (myosin) force-generating 

Ciliary Movement

• whip-like movement of cilia on cell surface
• surface of respiratory airways(cleaning of mucus through nasal and resp passages)
• inner surface of fallopian tubes (promotoe transport of ovum from ovary to uterus)

Ameboid movement

• movt of entire cell WBCs
• fibroblasts (move into damaged area for repair, actin-myosin filaments mediate cell locomotion)
• germinal skin cells (move toward wound opening
• embryonic cells

Control of Ameboid Locomotion

• chemotaxis-major initiator of ameboid movement
• results from appearance of certain chemicals in tissues
• positive chemotaxis-cell move towards chemotacic subs
• negative chemotaxis-cell movt away from source of chemotactic material

Cilium

• plays a major role in fluid movt
• rapid, forward-thrusting, whip-like movement of cilia pushes fluid adjacent to cell in the direction of the ciliary movt
• atp and appropriate ionic concentrations(Ca, Mg) required for continued beating of cilia

Gap Junctions (connexons)

• channels interconnecting cytosols of neighboring cells
• promote passage of inorganic ions, small molecules(cAMP), flow of electrical current
• permeability regulated by changes in ionic gradient, cAMP, H+, and membrane potential
• cell communication via direct interactions

Tight Junctions(Claudins)

• complex structure impedes passage of molecules and ions btw cells of epithelial monolayer
• can act as barriers (renal thick ascending loop), selective gates(renal proximal tubule), fences(epithelial plasma membrane seperated into apical and basolateral domains)
• cell communication via direct interactions

Adhering Junctions (Cadherins)

• maintenance of normal cell architecture
• organization of groups of cells into tissues
• provide information about nature and proximity of neighbors
• signaling role during organ development and remodeling
• cell communicate via direct interactions

Four Types of Extracellular

Signaling Molecules

• amines (epinephrine)
• peptides and proteins (insulin)
• steroids (estrogen)
• other small molecules (amino acids, nucleotides, ions, NO)

Major Classes of Physiological Receptors

• G protein-coupled Receptors (GPCR)
• Ion Channels
• Catalytic Receptors
• Nuclear Receptors

G Protein-Coupled Receptor (GPCRs)

• mediate cellular responses to hormones, NT, vasoactive peptides, ect
• single polypeptid chain with 7 membrane-spanning domains, an extracellular N-terminus(glcosylated) and cytoplasmic domain(hydrophilic amino acids)

G-protein Properties

• members of GTP-bindig proteins
• include heterotrimers (guanine nucleotide-binding α subunit plus associated β and γ subunits)
• α subunit-confers specific recognition to receptors/effectors
• β/γ subunits - confer membrane localization of G-protein trimer
• subunits have distinct tissue distribution
• interact with different receptor-effector system

4 major families of α subunits

(g-proteins)

• G_s α - activate AC (adenylyl cyclase)
• G_i α -inhibits AC
• G_q α - activate PLC (phospholipase C)
• G_12/13 α - couple to guanine nucleotide exchange factors for small GTP - binding proteins (Rho and Rac)

Adenylyl Clycase Function

• activated by alpha subunit
• converts ATP to cAMP
• cAMP activates PKA by binding to its two regulatory subunits, causing them to release the catalytic subunits

Protein Phosphatases reverse

action of kinases

• dephosphorylate proteins
• serine/threonine phosphoprotein phosphatases (PP) 4 types: PP1, 2a, 2b, 2c
• phosphotyrosine phosphatase (PTP)
• balance between kinase and phosphatase activity is critical

Phototransduction

• G protein acting via a phosphodiesterase
• light activates, alpha subunit then activates a phosphodiesterase
• converts cGMP to GMP
• breakdown of cGMP leads to closure of cGMP-dependent channels

Phospholipase Activation

• binding of hormone activates gprotein and alpha subunit activates the PLCβ
• PLCβ hydrolyzes PIP2 into IP3 and DAG
• DAG activates PKC
• IP₃ interacts with a receptor in the membrane of the ER, which allows the flow of CA2+ into the cytoplasm
• SERCA Ca2+ pumps CA2+ back into SR

Arachidonic Acid Metabolites

• G-protein coupled Second messengers
• released from membrane phospholipids by PLA₂ 
• Arachidonic Acid is metabolized to prostaglandins, prostacyclins, thromboxances vis cyclooxygenases
• there are direct pathways (PLA₂) and indirect pathways(PLCβ)

COX Products

• arachidonic acid metabolites
• prostaglandins, prostacyclins, thromboxanes
• vasoactive
• platelet aggregation, airway constriction
• inflammation, CVD

5-Lipoygenase Products 

• allergic and inflammatory diseases
• regulate ion channels (activate k-channels)
• Lekotriene
• arachiodonic acid metabolites

Epoxygenase Products 

• HETEs, EETs
• arachidonic acid metabolites
• enhance Ca²⁺ release from intracellular stores
• increase cell proliferation
• vasoconstriction of blood vessels

Ionotropic Receptors (Ion Channels)

(types)

Voltage Gated Ion Channels

• maintain electrochemical gradient required for maintenance of membrane potential
• ion transporter for Na+, K+, Ca2+, Cl-
• expressed in nerves, cardiac and smooth muscle cells

Voltage-activated Na-channel

• Depolarization opens then channel by altering position of voltage sensors
• hyperpolarization closes the channel
• found in nerve and muscle cells-responsible for robust generation of action potential resulting in membrane depolarization
• also found in pain neurons-serve as targets of local anesthetics which block the ion channel inhibiting membrane depolarization, thus blocking pain sensation

Ligand-Gated Ion Channels

• activated by binding of ligand to specific site in channel
• induces conformational change in the receptor
• leads to opening/closing of ion channel controlling ionic flow across cell
• ex: nicotinc Ach Receptor(skel. muscle), GABA receptor, Glutamate receptor, IP₃ sensitive Ca2+ channel(ryanodine receptor) responsible for Ca2+ release from ER

Catalytic Receptors

• 5 main classes
• receptor guanylyl cyclases: catalyze generation of cGMP from GTP
• Receptor serine/threonine kinases: phosphorylate serine/threonine residues on cellular proteins
• receptor tyrosine kinases(RTKs): phosphorylate tyrosine residues on themselves and other proteins
• tyrosine kinase-associated receptors: interact with non-membrane bound cytosolic tyrosine kinases
• receptor tyrosine phosphatases: cleave PO₄ groups from tyrosine groups of cellular proteins

cGMP signaling Pathways - GC

• membrane-bound GC: ANP receptor; single membrane spanning segment; extracellular domain binds ligand; intracellular domain-2 catalytic domains for GC activity
• soluble GC: activated by NO to produce cGMP

Natriuretic Peptide Receptors

(membrane bound GCreceptors)

• activated by ANP (lowBP), BNP (low bp, low cardiac hypertrophy, and low fibrosis), CNP (stimulate long bone growth
• ligand binding induces conformational change in receptor
• leads to receptor dimerization and activation

Soluble GCs

(GC receptors)

• receptor for NO signaling (v. imp in CV system for regulation of blood flow)
• conversion of GTP to cGMP -> increase intracellular levels of cGMP
• activation of cGMP-dependent kinases(PKG, PDEs)
• PKG activation leads to vasodilation in VSMCs

Receptor Serine/Threonine Kinases

• single membrane-spanning glycoprotein with serine/threonine kinase domain in cytoplasmic region
• 2 isoforms: Type I and Type II (ligand binding subunit)

Tgf-β receptor

• activated by Tgf-β superfamily
• exist as monomers in basal state
• ligand binding causes dimerization and phosphorylation of kinase domain of type I -> activation of receptor
• activated receptor phosphorylates gene regulatory protein known as "Smad"
• activation of Tgf-β plays important role in embryogenesis, promotes wound repair, regulate immune and endocrine functions

Receptor Tyrosine Kinases

• phosphorylate themselves in addition to cellular proteins
• ligand binding induces conformational change promoting formation of receptor dimers
• receptor dimerization allows autophosphorylation of cytoplasmic catalytic domains -> activation of receptor complex
• activated receptor also catalyze tyrosine phosphorylation on specific cytoplasmic proteins
• egs: insulin rec. IGF-1, EGF rec., PDGF, VEGF, FGF
• activation plays a role in cell survival, cell proliferation and differention

Tyrosine Kinase-associated Receptors

• receptors for cytokines and growth factors
• lack intrinsic tyrosine kinase activity
• intracellular domain binds non-receptor tyrosine kinases(JAKs, Srcs)
• few egs: cytokine receptors (ILs, γ-interferons, leptin, erythropoietin); receptors for growth hormone, prolactin

Cytokine Receptor (JAK/STAT)

• ligand binding induces receptor dimerization
• recruitment of JAKs to cytoplasmic domain of receptor
• JAKs phosphorylate STATs
• STATs then go to nucleus and regulate gene transcription

Receptor tyrosine phosphatases

• dephosphorylate tyrosine residues on cellular proteins
• required for lymphocyte activation
• egs. CD45 (located on T and B lymphocytes)

CD45 Receptor

• single-pass through membrane 
• glycosylated extracellular domain-functions as receptor for antibodies
• cytoplasmic domain-tyrosine phosphatase activity

Nuclear Receptors

• consists of superfamily of 48 receptors
• act as transcription factors that regulate expression of targe genes
• play role in various physiological processes
• homodimers (steroids), retinoic acid/vit. d/ thyroid hormone (heterodimers), fatty acids/bile acids, lipids (metabolic sensors)(FXR, LXR, PPAR)
• cytoplasmic (GR, MR), nuclear (ER, PR), DNA bound in nucleus (TR, RAR/RXR)

Classes of Nuclear Receptors

• GR: glucocorticoid receptor: GR/GR
• MR: mineralcorticoid receptor: MR/MR
• PR: progesterone receptor: PR/PR
• ER: estrogen receptor: ER/ER
• AR: androgen receptor: AR/AR
• VDR: vitamin d receptor: VDR/RXR
• TR: THyroid hormone: TR/RXR
• RAR: REtinoic acid receptor: RAR/RXR

Integrins

• examples of matrix receptors or cell matrix adhesion molecules
• comprise a large family of transmembrane proteins that link cells to components of the extracellular matrix at adhesion plaques

Pre and Post Ganglionic Synapses

• preganglionic are cholinergic(means they use Ach)
• post ganglionic synapse in parasympathetic are also cholinergic (Ach)
• post ganglionic synapse in sympathetic are adernergic(norepinephrine), cholinergic (sweat glands), and dopamine in renal? 
• nicotinic is also Ach?

Cholinergic Neurotransmission

• Choline is uptakin by CHT into thepresynaptic axon
• choline interacts with Acetyl Coa (choline acetyltransferase) and ACh is formed
• once synthesized Ach is uptaken by a storage vesicle through Vesicle associated transporter (VAT)
• Calcium channels open up and Ca interact with VAMPs (vessicle associated membrane protein) triggering vessicle fusion with membrane

Adrenergic Neurotransmission

• tyrosine is uptaken into terminal and hydroxalyzed into Dopa. Dopa then decarboxylated to Dopamine
• Dopamine then transported into vessicles by Vesicular Monamine Transporter(VMAT)
• Dopamine is hydroxylized to Norepinephrine(NE) 
• Calcium dependent release process like Ach
• 50 to 80% of NE is ruptaken into presynaptic terminal via NE transporter 
• has degrading enzyme monamine oxidase in synapse and COMT in tissues for NE
• adrenal medulla can methylate NE to epinephrine

Cholinergic Receptors

• muscarinic(muscarine) (all post ganglionic cholinergic neurons) cells in CNS, heart and smooth muscle, glands and endothelium (gprotein coupled receptors)
• nicotinic(nicotine) autonomic preganlionic synapse, skeletal muscle  neuromuscular junction (ion-channel receptors)
• both activated by Ach

Adrenergic Receptors

• alpha receptors(α1 and α2) and beta receptors (β1 and β2)
• α1 - vascular smooth muscle cells(VSMC)
• α2 - sympathetic nerve terminal, VSMC
• β - mainly in heart, blood vessels, kidney, lungs

Norepinephrine and Epinephrine

Differences

• norepinephrine mainly activates alpha recptors and excites beta receptors to a lesser extent
• epinephrine excites both alpha and beta receptors
• Epinephrine has greater cardiac stim., 5-10X greater metabolic effect and increases liver/muscle glycogenolysis, glucose release into blood, and activity/excitability of body
• norepinephrine has stronger constriction of blood vessels

Muscarine

M1, M3, M5

• agonist is Ach
• gprotein is G_oq and the linked enzyme is PLC
• the secondary messengers are IP3 and DAG

Muscarine

M2, M4

• agonist is Ach
• G_αi and G_αo and the linked enzyme is AC
• secondary messenger is a decrease in cAMP

Adenosine Triphosphate (ATP)

• non classic neurotransmitter in ANS
• co-localized w/ NE in postganglionic sympathetic vasoconstrictor neurons 
• induces vasoconstriction of VSMC via P₂ purinoreceptors(P_2x ligand gated ion channel receptors; P_2Y, P_2U GPCRs)

Nitric Oxide

• non-classical neurotransmitter in ANS
• synthesized from L-Arginine by enzyme Nitric Oxide Synthase (NOS)
• NOS found in pre and post ganglionic symp and parasymp neurons
• largely synthesized in vascular Epithelial cells

Adrenal Medullae and Sympathetic NS

• secretion of medullary hormones is 80% Epinephrine and 20% Norepinephrine
• Ep and NE act directly on blood vessels leading to vasoconstriction(alpha adrenergic receptors)
• organ system effects of circ. Ep/NE similar to direct symp stimulation
• Ep/NE have slow removal time from blood so prolonged effects(5-10X) than direct symp 

Sympathetic Nervous System: 

Mass Discharge

• increases: arterial pressure
• blood flow to active muscle concurrent w/ decreaed flow to organs not needed 
• rates of cellular metabolism and blood glucose concentration
• liver/muscle glycolysis
• muscle strength
• mental activity
• blood coagulation rate

Sympathomimetic Drugs

• drugs that act on adenergic effector organs(Ep/NE)
• vary in duration of action, degree and interaction with adrenergic receptor subtypes
• drugs w/ indirect sympathomimetic action cause release of NE from its storage vessicles in sympathetic nerve endings (ephedrine, amphetamine)

Parasympathomimetic Drugs 

• mimics the effects of Ach (cholinergic)
• direct acting bind directly to and activate cholinoreceptors(muscarinic and nicotinic)
• indirect action: act inderectly by inhibiting acetylcholinesterase, in turn inhibiting hydrolysis of endogenous Ach

Quaternary Alcohols

(Edrophonium)

• reversibly bind to active site of AchE, prevent Ach acces, enzyme-inhibitor complex relatively unstable, short lived(2-10 mins)
• indirect cholinomimetics

Carbamates

(neostigmine, physostigmine)

• reversibly bind AchE to form a carbomoylated enzyme which is slowly hydrolyzed, therefore more prolonged duration of action (30min-6h)
• indirect acting cholinomimetics

Organophosphatates

(parathion, Malathion)

• indirect acting cholinomimetics
• undergo initial binding and hydrolysis by enzyme resulting in phosphorylated active site
• phosphorus enzyme complex extremely stable(irreversible inhibitor)
• very slowly hydrolyzed (hundreds of hours)

Cholinergic Blockers

• muscarinic receptor antagonis are plant based (belladonna alkaloids eg. atropine; scopolamine) and synthetic agents (ipratropium, tropicamide)
• nicotinic receptor antagonists are neuromuscular junction blockers (succinylcholine tubocurarine) or ganglionic blockers (hexamethonium)

Drugs blocking Adrenergic Activity

• reserpine inhibits syn/storage of NE in symp nerve endings
• guanethidine blocks release of NE from symp endings
• phentolamine,phenoxybenzamine blcok symp alpha receptors
• propanolol, metroprolol block sym beta receptors

Factors That Effect Net Diffusion

• concentration 
• Membrane Electric potentional (nernst potential EMF=+,-61 log C1/C2) 
• pressure differences(eg blood capillaries -20mmHg)

Active Transport

• primary active transport: sodium-potassium pump, calcium ions, hydrogen ions
• secondary active transport: co-transport (transport of glucose and amino acids along with sodium ions) and counter transport(sodium counter transport of calcium and hydrogen ions)

Sodium-Potassium Pump

(Na/K ATPase)

• made up of two globular proteins(large alpha and small beta)
• 3 Na sites and 2 K sites
• ATPase activity
• beta subunit anchors pump to membrane
• controls cell volume and action potential
• ouabain(digoxin) irreversible inhibitor of pump
• cell swells if pump does not control leak channels (more permeable to potassium)

Calculating Membrane Potential

• EMF=61xlog c1/c2 
• c1/c2= inside/outside
• if a positive is leaving it is negative if it is coming in it is positive
• for multiple ions you can combine them 

Distinguishing Ion Channels

• electrophysiology(sensitivity, voltage dependence, gating)
• pharmacological ligands(toxins: inhibitors)
• physiological ligands(agonists nicotinic acetylcholine)
• intracellular messengers(calcium activated k+ channels)
• sequence homology(Transient Receptor Potential(TRP) channels (nonselectivly permeable to cations), connexins)

L-Type Calcium Channels

• voltage gated long lasting channels
• responsible for excitating-contraction coupling of skeletal, cardiac and smooth muscles
• opposed by potassium channels
• activated by PKA which is activated by cAMP which is activated by beta one E/NE receptor on a gprotein

Funny Channels

• also funny current, found in nodes of heart 
• responsible for starting diastolic depolarization
• supplies inward current
• mixed sodium-potassium current
• slowly activating on hyperpolaization at diastolic range
• work along with Transient(T) type calcium channels as pacemaking of heart (membrane does not have to go positive for them to activate about -20)

Anesthetics

• can be inhibitors or blockers of voltage gated channels
• an example is cocaine and Na channels
• most block Sodium channels

Hyperkalemic periodic paralysis

• caused by a mutation of Thr to Met
• most result in muta something bullshit
• this can happen in any voltage gated ion channel?

Modulators of Voltage Gated

Calcium Channels

• 1,4-dihydropyridines (inhibit ltype calcium channels)
• 2 types of 1,4 are nitrendipine and Bay K8644
• phenylalkylamines
• benzothiazepines

Ionotropic and Metabotropic 

Receptors

• recepotrs for nuerotransmitters (ex is Ach)
• ionotropic if the transmitter induces an ionic current (can also be nicotinic) (ex is skeletal muscle)
• metabotropic if it activates a G-protein (muscarinic)(ex is heart)

Acetylcholine Gated Channel

Myasthenia Gravis

• causes muscle paralysis in 1:20,000 people
• develops antibodies to Ach Receptors
• fatigued and weak 
• severe cases die from paralysis or resporitory muscles
• treated by inhibiting acetylcholinesterase with DFP or physostgmine 

Agonists of Nicotinic ACh Receptors

• ACh
• carbachol
• nicotine
• succinylcholine

Antagonists of Nicotinc ACh

Receptors

• tubacurarine
• pancurenium

Muscle Fibers

• each fiber 10-80 Microns in length
• each fiber contains 100s to 1000s of myofibrils
• each myofibril contains myosin(1500) and actin (3000) filaments

PMCA

• plasma membrane Ca2+ ATPase
• exchange one H+ for one Ca2+ for every ATP hydrolyzed
• usually for pumping Ca2+ out of the cell or into a SR

Sarcomere

• spans from Z band to Z band (each band in a I band)
• M line is in the middle of the sarcomere (contained in H band)
• A band goes from I band to I band
• six actin bands and 4 myosin bands 

Excitation-Contraction Coupling 

in Skeletal Muscles

• membrane depolization opens Calcium channels
• the Ltype calcium channels on the T tubule physically couple with channels on SR (via ryanodine receptors)
• activate calcium channels on SR
• calcium from Ltype not required in skeletal but are required in cardiac muscle to release calcium from SR
• calcium attaches to troponin, exposing myosin binding site

Titin

• large protein in body
• very springy
• extends from z to m line
• keeps the side by side interactions of mysoin and actin
• keeps myosin filament attached to z line?

Sarcoplasm

• intracellular fluid between myofibrils
• k+, Mg2+, phosphate and enzymes
• sarcoplasmic reticulum: ER of the skeletal muscle

Myosin Molecule

• 2 large heavy chains: one end wrap spirally to form double helix tail
• other end folds bilaterally into a globular polypeptide head
• head functions as ATPase
• 4 light chains(2 for each head): control function of head during contraction

Thin filaments

(muscle fibers)

• double helix of actin
• double helix of tropomyesin
• troponin complex (T(tropomyesin), C(calcium), and I(actin))
• troponin c has 4 binding sites for Ca but only 2 are used
• binding of Ca causes conformational change

Cross Bridge Cycle

• when ATP binds to myosin head it releases myosin from actin (released state)
• ATP hydrolyzed to ADP and Pi and head moves from 45 to 90 degrees (cocking phase)
• then binds to actin molecule (crosbridge phase)
• then phosphate leaves and head goes from 90 back to 45 degrees (powerstroke)

Calcium Removal 

From Cytoplasm

• Ca2+ pump (ATPase) into the SR
• in SR calcium is bound to calreticulin and calsequestin 
• Ca2+ pump (ATPase) that pumps calcium into the ECF and (brings in a proton)?
• an Na-Ca exchanger

Sources of Muscle Contraction

Energy

• ATP in muscle fiber
• phosphocreatine
• glycolysis of stored glycogen: in the absence of oxygen (rate of ATP formation is 2.5 times faster)
• oxidative metabolism(slow sustained contraction)

Slow Muscles Fibers

• type 1, Red Muscle
• small fibers
• innervated by smaller nerve fibers
• extensive blood vessel system
• increased number of mitochondria
• contain large amounts of myoglobin
• oxidative metabolism

Fast Muscle Fibers

• Type II muscle fibers, White Muscle
• large fibers for large contraction
• extensive sarcoplasmic reticulum
• less extensive blood vessel system
• fewer mitochondria
• deficit in myoglobin
• glycolisis

Muscle hypertrophy

• total mass of muscle increases
• fiber hpertorphy: increase in actin and myosin filaments (common)
• fiberhyperplasia:rare condition increasing muscle fibers

Muscle Atrophy

• total mass of the muscle decreases
• from not using muscles

Phospholamban

• regulates calcium pumps in skelatal and cardiac muscle
• inhibits cardiac SERCA (SR Ca2+ ATPase pump)
• inhibits when not phosphorylated
• key regulator in distolic function
• phosphorylated by PKA (which is activated from beta adrenergic agonists like epinephrine

Smooth vs Skeletal Muscle

• smooth is small fibers and skeletal is large
• both same contractile apparatus
• myosin and actin filaments
• physical arrangement differ

Types of Smooth Muscle

• distinct for each organ: physical dimensions, organization-bundle or sheets, response to different types of stimuli, characteristics of innervation, function
• two major types: multi-unit (innervated seperatly) and unitary smooth muscle (works as a group)

Multi-Unit Smooth Muscle

• composed of discrete, seperate SM fibers
• each fiber operates and is innervated independently
• covered by Basement like membrane
• contracts independently and conrolled by nerve signals
• ex is ciliary muscle of the eye

Unitary Smooth Muscle

• syncytial or visceral because you find mostly in visceral organs
• fibers arranged in bundles or sheets and membranes adherent to each other
• joined by gap junctions
• contract as synchronized/syncytial
• found in GI, uterus, blood vessels

Contractile MEch of SMooth muscle

• actin and myosin filaments and ATP and calcium here
• no sarcomere, filaments attached to dense bodies
• no troponin complex, Ca
• coupling of E-C and duration can be varied

Smooth Muscle Cross Bridge Cycle

• calcium released and binds to calmodulin (4 Ca)
• calmodulin binds to myosin light chain kinase(MLCK)
• MLK then activates the myosin light chain regulatory protein (phosphorylation) that activates the myosin head

Comparison of Smooth Muscle and Skeletal Contraction

• slow cycling of the myosin cross pridges 
• low energy requirement
• slowness of onset of contraction and relaxation of total smooth muscle tissue (slower_
• maximum force of contraction greater
• latch mechanism: prolonged holding of contraction
• stress-relaxion of smooth muscle: can go back to original force of contraction

Pharmacomechanical Coupling of Smooth muscle

• vasoconstrictor agonist is activated
• GPCR activates phospholipaseC
• this takes PIP2 and makes IP3 and DAG
• IP3 then causes the Sarcoplasmic reticulum to release its Ca2+

Varicosities

• innervation of smooth muscle
• secrete bothe ACh and Nor-epinephrine
• excitory and inhibitory
• different receptors for each

Bachman's bundle

• interatrial tract
• allows impules and action potentials from right atrium to go to left atrium

Time to go From 

SA -> AV node

• 3 hundreths of a second
• 0.03 seconds
• around 10 hundreths of a second for entire atrium to be polarized ( left and right)
• about .12-.16 s delay once it reaches the AV node till when it leaves AV node

Spontaneous Depolarization

• I_f or funny current allows sodium and maybe calcium in
• time dependent closure of potassium channels starts the process
• action potential starts when Ltype calcium channels open
• both SA and AV node (AV node is slower)

Cardiac Muscle Depolarization

• unlike the calcium in the nodes, the muscles depolarization starts from rapid infllux of Na+
• plataue phase then caused by the L-type calcium channels

Chronotropic response

3 Ways to Change Heart Rate

• change in rate depolarization
• shift maximum diastolic potential (how hyperpolarized, low the thing goes)
• shift in threshold (how high it needs to go for action potential)

Pheochromocytoma

• tumor on adrenal gland
• causes secretion of catecholamines which activate beta adrenergic receptors 

EKG Explaination 

• SA node: before p wave(does not register)
• AV node: P Wave
• bundle of his, branches, purkinje: btw P and Q wave
• Vetricles:QRS and T waves?
• ST segment is calcium entry (plataue phase)
• t wave is repolarization

Phase 1

Vascular Events

Phase 2

Valvular Events

• closing of AV Valves
• isovolumetric ventricualr contraction
• all valves are closed
• systole

Phase 3

Valvular Events

• opening of semilunar valves
• rapid ventricular ejection(fast muscle shorteing)
• decreased ventricular ejection (slowing muscle shortening)
• systole

Phase 4

(valvular Events)

• closing of semilunar valves
• isovolumetric ventricular relaxation (w/ all valves closed)
• diastole

Ejection Fraction

• EF= SV/EDV
• SV is systolic volume (smaller number)
• EDV is end diastolic volume (bigger number)

Heart Sounds

• 1st heart sound: S₁ - movement of the mitral valve/closure of AV valves (hear turbulance of blood)
• 2nd heart sound: S₂ - closure of the Semilunar valve (aortic in graph) 
• S₃ sound you might hear during diastole (ventricular filling) (might not hear it)
• S₄  - associated with atrial contraction (pushing blood across mitral valve

Jugular Venous Pressure Changes

• a wave: right atrial contraction
• C wave: right ventricule contracts
• V wave is the filling of the right atrium
• respiratory cycle causes changes in venous pressure

Preload

• load that is imposed on the heart before it begins to contract
• volume at end of diastole (about 120 ml is normal)

After Load

• the load that prevents muscle shortening
• pressue thats opposing the opening of the aortic valve
• resists the pressure of the aorta

Right vs left heart times 

• mitral valve closes before the tricuspid valve (contraction starts on left side before right side)
• isovoumetric contraction is longer on the left side then the right side (takes heart longer to develop pressure in left ventricle to open up aortic valve)
• right ventricle spends more time ejecting blood then the left
• takes heart longer to relax on left because it has higher pressure

Left Atrial Pressure and

Preload

• left atrial pressure when the mitral valve is open is equivalent to left ventricular diastolic pressure
• left atrial pressure is giving us an index of how much blood is in the left ventricle at the end of diastole

Contractility

• sympathetic nervous system increases
• as it goes up so does function
• load independent measure of function
• preload does not improve contractility
• elastanse is the slope of contractility 
• more stiff ventricle more contractile and visa versa
• higher stroke volume for same level of preload if more contractile

Increasing After load

• has to increase pressure before aortic valve opens
• higher total pressure development 
• stroke volume is smaller 
• total work would be about the same though
• (high blood pressure)
• ejection fraction would be down too (compromised ventricular function