Lecture 2: Principles of Cellular Physiology

Reading: chapter 2 chapter 3: membrane structure and composition, pgs 52-58 (pgs 56-62 if using 5th edition)

Levels of Organization (Figure 2-1)

Plasma membrane Nucleus Cytoplasm
Organelles endoplasmic reticulum Golgi complex lysosomes peroxisomes mitochondria vaults Cytosol Cytoskeleton microtubules microfilaments intermediate filaments microtrabecular lattice

Plasma membrane: Thin membrane enclosing each cell (Figure 3-1)

composed of phospholipid bilayer embedded with proteins and carbohydrates (Figures 3-2, 3-3) separates intracellular and extracellular spaces serves as a barrier to diffusion

membrane proteins
can selectively transport molecules and ions can act as receptors to signal responses by the cell can form adhesions and junctions with other cells

Nucleus: Membrane bound organelle containing the genetic material

Deoxyribonucleic acid (DNA): genetic material
directs protein synthesis; serves as genetic blueprint during cell replication Ribonucleic acid (RNA): carries out protein synthesis

messenger RNA
DNAs genetic code is transferred to mRNA via transcription and the message

exits the nucleus

ribosomal RNA
participates in reading the message and translating the message into the appropriate protein sequence (translation)

transfer RNA
transfers the appropriate amino acid in the cytoplasm to their designated site in the protein being constructed

Cytoplasm: portion of cells interior not occupied by the nucleus

Organelles
membrane-enclosed structures that carry out specific functions

6 main types
similar in all cells

Endoplasmic reticulum (ER)

continuous fluid filled network of membranous tubules (Figure 2-2)

rough ER
ER membrane covered with ribosomes that synthesize and release proteins into the ER lumen. The protein products can be secreted or transported to sites within the cell.

ribosome
constructed in the nucleus and programmed to carry out the synthesis of a single type of protein

smooth ER
ER membrane lacking ribosomes that serves to package and transport molecules synthesized in the rough ER. Portions of sER bud off to form transport vesicles that move to the Golgi complex for further processing

Golgi complex
sets of flattened, membrane-enclosed sacs stacked in layers and specialized for processing raw materials into finished products, and directing the products to their destinations including secretion

exocytosis
membrane enclosed vesicles containing finished products fuse with the plasma membrane thereby secreting the contents. (Figure 2-3, 2-4, 2-5)

Lysosomes
membrane-enclosed sacs derived from the Golgi complex containing hydrolytic enzymes to digest and remove unwanted material. These organelles fuse with endocytotic vesicles to breakdown internalized material.

endocytosis
the process by which extracellular material is brought into the cell (Figure 2-8; 2-9)

pinocytosis
invagination of the plasma membrane to form a pouch and internalize extracellular fluid

receptor-mediated endocytosis phagocytosis

invagination of the plasma membrane to form a large vesicle and internalize large particles such as bacteria or tissue debris

Peroxisomes
membrane-enclosed sacs containing oxidative enzymes which act to remove hydrogen from toxic molecules. This leads to the formation of hydrogen peroxide (H2O2) which is degraded by catalase contained within the peroxisomes catalase An antioxidant enzyme that decomposes H2O2 into H2O and O2.

Mitochondria
oval double membrane-enclosed organelles containing the enzymes responsible for aerobic metabolism and the production of cellular energy in the form of adenosine triphosphate. (Figure 2-9; 2-10)

adenosine triphosphate (ATP)

molecule composed of adenosine bound to three high energy phosphate groups that serves as the energy sources for all cellular functions. Energy is released when ATP is converted to ADP and phosphate (Figure B-18). ATP is used for chemical synthesis, membrane transport, and mechanical work.

Glycolysis
sequence of enzymatic reactions carried out in the cytosol in which a glucose molecule is converted into 2 molecules of pyruvic acid and 2 molecules of ATP are synthesized. This reaction sequence is responsible for anerobic metabolism (Figure 2-10; 2-11). The pyruvic acid molecules are transported into the mitochondrial matrix where each is enzymatically converted to a molecule of Acetyl-CoA and one molecule of CO2, and one molecule of NADH is synthesized

Citric acid cycle

sequence of enzymatic reactions carried out in the mitochondrial matrix in which the energy stored in one molecule of Acetyl-CoA leads to the formation of one molecule of ATP, two molecules of CO2, three molecules of NADH, and one molecule of FADH2. (Figure 2-11; 2-12) NADH - (nicotinamide adenine dinucleotide-H) a derivative of B-vitamin niacin which acts as an energy source by donating electrons. FADH2 - (flavine adenine dinucleotide-H2) a derivative of B-vitamin riboflavin which acts as an energy source by donating electrons.

Electron transport
sequence of enzymatic reactions requiring O2 that are carried out in the inner mitochondrial membrane in which the donation of high energy electrons from

NADH and FADH2 lead to the production of ATP and H2O. Oxygen serves as the final electron acceptor and combines with H+ ions to form H2O. For each NADH molecule, 3 ATP molecules are formed and for each FADH2 molecule, 4 ATP molecules are formed (Figure 2-12; 2-13)

Summary
Glycolysis: Glucose => 2 Pyruvic acid + 2 ATP Pyruvate Metabolism: 2 Pyruvic Acid => 2 Acetyl-CoA + 2 CO2 + 2 NADH TCA cycle: 2 Acetyl-CoA => 4 CO2 + 2 ATP + 6 NADH + 2 FADH2 Electron transport: 8 NADH => 24 ATP + 4 H2O; 2 FADH2 => 8 ATP + 2 H2O Combined: 1 glucose => 36 ATP + 6 CO2 + 6 H2O

Vaults: Octagonally shaped proteinaceous organelles which may function to transport

molecules, such as mRNA, to sites within the cytoplasm (Figure 2-15; 2-16).

Cytosol: Semiliquid portion of the cytoplasm in which at least three major functions
take place:

Enzymatic regulation of intermediate metabolism

intracellular chemical reactions involving the degradation, synthesis and transformation of small molecules such as sugars, amino acids, and fatty acids.

Ribosomal protein synthesis

proteins for use in the cytosol and elsewhere are synthesized on free ribosomes

Storage of fat and glycogen

excess nutrients are converted into fat and glycogen for storage in the cytosol

Cytoskeleton
Complex intracellular protein network that provides structural support and the capability for transport of material and cellular movement. Composed of 4 major components.

microtubules
long, hollow, unbranched proteinaceous tubes composed primarily of tubulin and responsible for maintaining cell shape, and for controlling cellular movements such as vesicular (axonal) transport, movement of cilia and flagella, and distribution of chromosomes during cell division.

tubulin
small globular protein (Figure 2-17; 2-18)

axonal transport
bidirectional movement of large molecules and vesicles along the axon of neurons (Figure 2-18; 2-19).

cilia
motile, hair-like protrusions allowing cells to move materials across their surface. They line the respiratory airways and the oviducts. (Figure 2-20; 2-21)

flagella
single, long whip-like appendage that enables cells to move thru their environment. Form the tails of spermatozoa.

microfilaments
filaments composed of two strings of actin molecules that function in cellular contraction and mechanical support of cellular extensions such as microvilli.

intermediate filaments
irregular thread-like protein molecules that provide structural support for cellular components subject to mechanical stress, such as neuronal extensions, muscle cells, and skin cells

microtrabecular lattice
fine interlinked filaments that pervade the cytoplasm and are connected to the inner layer of the plasma membrane. Forms a lattice that suspends other components of the cytoskeleton and organelles. Acts as the cells skeleton by providing shape, rigidity and structural support. (Figure 2-24; 2-27)

Lecture 3: Membrane Signaling and Transport

Reading: chapter 3: introduction through membrane transport, pgs 52-73 (pgs 65-87, if using 5 th edition) chapter 4: intercellular communication and signal transduction, pgs 111-113

Intercellular Communication
Gap junctions
Communicating junctions that permit the passage of small molecules

Direct signaling
Extracellular protein-protein interactions

Extracellular chemical messengers (Figure 4-21; 3-7)

paracrine hormone neurotransmitter neurohormone

How are extracellular chemicals secreted by one cell detected by another? 1. G protein coupled receptors, coupled to 2nd messengers pathways e.g. cAMP, IP3 pathways
These pathways ultimately bring about a cellular response by altering the structure and function of proteins (Figure 4-24, 4-25; 3-8, 3-9). 2. Activation of ion channels Ion channels are membrane proteins that permit small soluble ions such as Na, K, Ca and Cl to pass across the plasma membrane. There are two major types: leak channels, which are always open, and gated channels, which open and close in response to various stimuli. Different types of gated channels are gated by changes in membrane voltage, mechanical deformation, or binding of chemical messengers. For the latter category, there are two types: Ionotropic signaling Activation of ion channels by direct binding of extracellular chemical messenger Metabotropic signaling Activation of ion channel via 2nd messenger pathway.

Membrane Transport
The movement of substances across the plasma membrane for the purpose of maintaining homeostasis or carrying out specific functions. The plasma membrane is selectively permeable to certain substances. Therefore some substances can move passively across the plasma membrane while others must be transported. Selective permeability (Figure 3-2). The chemical structure of the plasma membrane (i.e. bilayer of phospholipids)

makes it selectively permeable to lipid soluble substances or to small molecules and ions. Polar molecules or macromolecules cannot permeate the membrane.

Passive transport
Movement of substances across the plasma membrane without expenditure of cellular energy, via direct permeation. This type of transport can occur by movement along an electrical or chemical gradient or by carrier mediated mechanisms.

Active transport
Movement of substances across the plasma membrane that requires the expenditure of cellular energy. This process may occur for substances that must be transported against their electrochemical gradient, or for substances for which the plasma membrane is impermeable (e.g. sugars, amino acids, proteins). There are two general types of active transport, membrane pumps and vesicular transport (next page).

Unassisted Membrane Transport

Diffusion down a concentration gradient
random movement of molecules from regions of higher to lower concentration (Figure 3-7; 3-11).

Movement along an electrical gradient

An electrical gradient (i.e. voltage difference) is caused by the spatial separation of electrical charge that is created when concentration differences among ionic molecules are established. Molecules that are electrically charged (i.e. ions) will move in a direction along an electrical gradient that is determined by their polarity (i.e. positive or negative charge).

Electrochemical gradient
The combined force of concentration and electrical gradients that act on molecular and ionic substances. Diffusion through a membrane (Figure 3-8; 3-12)

Rate of diffusion depends on several factors:

magnitude of the concentration gradient permeability of the membrane surface area of the membrane molecular weight of the substance distance over which diffusion takes place

Osmosis
A special case of passive transport occurring when water diffuses down its concentration gradient to regions of higher solute concentration. When this process occurs across the selectively permeable plasma membrane the diffusion of water can exert osmotic pressure. (Figures 3-10, 3-11, 3-12, 3-13; 3-15 thru 3-18)

Case 1: membrane permeable to both water and solute. Case 2: membrane permeable to water, impermeable to solute. Case 3: same as case 2, different initial conditions.

osmotic pressure
The magnitude of opposing hydrostatic pressure that is necessary to stop osmosis. This pressure is proportional to the difference in solute concentrations that exist across the plasma membrane. Because of this effect, solute concentrations in the intracellular and extracellular spaces are kept in careful balance to avoid substantial changes in cellular pressure or volume.

Carrier Mediated Transport

This process occurs when a substance is bound to a transmembrane protein that undergoes a conformational change and the substance is released on the other side of the membrane. It can be passive or active depending on the type (see below).

Facilitated diffusion
The binding of the substance can directly cause the protein to change its conformation and thereby facilitate its diffusion across the membrane (Figure 3-14; 3-19). Because the energy of binding is used to induce the conformational change, this is a passive process. Alternatively, the conformational change can be induced by a separate energy-dependent process, such as phosphorylation. This is an active process. The latter mechanisms are often referred to as membrane pumps.

Membrane pumps
Active transport of one or more ionic species against their electrochemical gradients. Examples include the hydrogen-ion pump and the Na+/K+ ATPase

Hydrogen-ion pump
Active transport protein moves H+ against its concentration gradient (Fig 3-16; 3-21) *Animation*

Na+/K+ ATPase
Active transport protein that transports Na+ out of the cell and K+ into the cell . Three Na+ ions are transported out for every two K+ ions in (Figure 3-17; 3-22). This pump is present in every cell and has 3 main functions: maintenance of Na+ and K+ concentration gradients maintenance of osmotic balance establishment of energy gradients are used for co-transport of other substances

Vesicular transport
The movement of large polar molecules or macromolecules across the plasma membrane by means of endocytosis and exocytosis.

Lecture 4: Resting Potential and Graded Potentials

Reading: chapter 3: membrane potential, pgs 73-80 (pgs 87-93, if using 5 th edition) chapter 4: introduction through graded potentials, pgs 84-89 (pgs 98-102, if using 5th edition)

Resting Membrane Potential

This is the voltage difference that exists across the plasma membrane, expressed in millivolts, when the cell is at rest (i.e. no perturbing influences)

Charge separation across a membrane creates membrane potential

(Figure 3-19)

How does the cell create charge separation?

1. Establishes and maintains concentration gradients for key ions (Na+, K+, A-) 2. Ions diffuse through the membrane down their concentration gradients 3. Diffusion through the membrane results in charge separation, creating a membrane potential (electrical gradient) 4. Net diffusion continues until the force exerted by the electrical gradient exactly balances the force exerted by the concentration gradient

Concentration gradient (Table 3-3) Macromolecular anions (A-) High intracellular concentration of nucleic
acids and proteins which carry a net negative ionic charge. Na+ High extracellular concentration due to the Na+/K+ ATPase (Figure 3-23; 3-29) K+ High intracellular concentration due to the Na+/K+ ATPase (Figure 3-23; 3-29) Leak channels: Permit ions to flow down concentration gradients Na/K ATPase: Establishes and maintains concentration gradients

Permeability of the membrane A- Impermeable, nearly infinite resistance Na+ Low permeability, relatively high resistance K+ High permeability, low resistance Diffusion of K+ and Na+ ions through the membrane (Figure 3-20, 3-21;
3-26, 3-27) Because the resistance to the flow of K+ is low, and its concentration gradient is high, K+ tends to flow out of the cell down its concentration gradient. Because K+ ions are positively charged and the inside of the cell is negatively charged, there is an opposing electrostatic force that attracts the K+ ions back into the cell. When these two opposing forces, the concentration gradient and the transmembrane voltage, become equal and

opposite, there is no net flow of K+ ions across the membrane. The transmembrane voltage at this point is referred to as the equilibrium potential for that ion. The equilibrium potential for a particular ionic species can be calculated using the Nernst Equation (Vm = 61 log[co]/[ci]), where Vm is the transmembrane voltage, co and ci are the extracellular and intracellular concentrations of the ionic species, respectively. This equation describes the membrane voltage that exactly counterbalances the concentration gradient for a particular ionic species:

EK = -90 mV ENa = +60 mv *If the permeability of the membrane to a particular ion transiently increases, the Vm will shift towards the equilibrium potential for that ion. Magnitude of the resting potential
Most (not all) of the resting membrane potential, is due to the flow of K+ ions. This is because the resting permeability of the membrane is highest to K and so Vm tends to be dominated by EK (-90 mV). Two other factors contribute to the resting membrane potential in neurons. The first is passive flow of Na+ down its electrochemical gradient. Although the plasma membrane has a low permeability to Na+, there is a high electrochemical gradient acting to pull Na+ into the cell. Therefore the passive flow of Na+ into the cell tends to make the transmembrane potential more positive. The Na+/K+ ATPase transports 3 Na+ ions out of the cell for every 2 K+ ions it transports into the cell. This results in a net movement of positive charge out of the cell, making the inside of the cell more negative. Because of this property, the Na+/K+ATPase is often referred to as an electrogenic pump and it makes a small contribution to the resting membrane potential. The end result of all of these processes acting together tends to give most neurons a resting membrane potential around -65 mV (Figure 3-22; 3-28).

Neurons (Figure 4-10; 4-11)

Soma: cell body of a neuron Dendrite: membranous processes extending from the soma that receive
synaptic inputs from other neurons Axon: a single specialized membranous process extending from the soma that conducts action potentials axon hillock - the initial portion of the axon extending from the soma. The site at which action potentials are most commonly generated. axon terminal - the distal end of axonal fibers where chemical synaptic transmitter is released.

Graded Potentials
Local changes in membrane potential that decay over short distances. Can occur as depolarizations or hyperpolarizations and most often result from chemical synaptic transmission (Figures 4-1, 4-2, 4-3, 4-4). depolarization - decrease in membrane polarization to more positive values than rest. Most often produced by excitatory synaptic transmission. hyperpolarization - increase in membrane polarization to more negative values than rest. Most often produced by inhibitory synaptic transmission.

Lecture 5: The Action Potential

Reading: chapter 4: action potentials, pgs 89-101 (pgs 103-116, if using 5th edition)

Action Potential
Brief all-or-nothing reversal in membrane potential (spike), lasting on the order of 1 millisecond, that is brought about by rapid changes in membrane permeability to Na+ and K+ ions. Initiated in axonal or somatic membranes when the membrane potential is depolarized beyond a threshold potential and can propagate along axonal (and dendritic) membranes at a velocity that is determined by several factors. Because of their ability to propagate, action potentials are the primary mechanism used by the nervous system to transfer information over long distances (i.e. 0.1 - 1000 mm) (Figure 4-6).

Voltage-gated channels
Action potentials occur when Na+ and K+ channels in the plasma membrane open in response to depolarization. Because of their sensitivity to membrane depolarization these channels are referred to as voltage-gated channels (Figure 4-7).

Initiation of action potential

Once the threshold potential is crossed, depolarization occurs via a positive feedback cycle (Figure 4-8).

Events underlying the rising (Na+) and falling (K+) phases of the action potential (Figure 4-9 in 5th edition only) *Animation* Summary of permeability changes and ion fluxes (Figure 4-9; 4-10). Voltage-gated Na+ channel
Opens (activates) quickly (< 0.5 ms) in response to depolarization, allowing Na+ to flow down its electrochemical gradient into the cell. This movement of positive charge into the cell causes further depolarization, which in turn causes more Na+ channels to open, which leads to more depolarization. This is an example of positive feedback, and this property of the Na+ channel is responsible for the all-or-nothing character of the action potential. Voltage-gated Na channels have both an activation gate (main gate) and an inactivation gate (ball and chain). The channel transitions between three conformations: deactivated (closed but capable of opening), where the activation gate is closed and the inactivation ball is not lodged in the pore. In this state, no current flows. Opening can occur in response to depolarization; activated (open), where the activation gate is open and the inactivation ball is not blocking the pore. Current flows thru the channel; inactivated (closed and incapable of opening), where the activation gate is open but the inactivation ball has swung in to block the pore. No current flows.

In addition the channel is not capable of opening in response to depolarization, because the ball does not respond to depolarization. Removal of inactivation (dislodgement of the ball) is dependent on repolarization back to ~ resting potential. threshold This is the membrane potential which, when reached, leads inevitably to the occurrence of a spike. inactivation Occurs more slowly than channel opening (activation) and contributes to the termination of a spike absolute refractory period A brief period during a spike in which a second spike cannot be generated due to inactivation (Figure 4-13; 4-14). Voltage-gated K+ channel Opens in response to depolarization with a time course that is slower than the Na+ channel. This allows K+ ions to flow out of the cell down their electrochemical gradient, which in turn leads to repolarization of the membrane potential as positive charge leaves the cell. Voltage-gated K channels have only an activation gate, and therefore exist in either open (activated) or deactivated (closed) states. Repolarization is necessary for their deactivation. after hyperpolarization (AHP) A brief period at the end of a spike in which the membrane potential is more negative than rest. relative refractory period A brief period following a spike during which a higher intensity stimulus is needed to generate a second spike (Figure 4-13; 4-14). Na+/K+ ATPase Restores the concentration gradients for Na+ and K+.

Propagation
Action potentials propagate when locally generated depolarizing current spreads to adjacent regions of membrane causing it to depolarize (Figure 4-11; 4-12). Conduction velocity is proportional to axonal diameter and is increased by myelin.

Contiguous conduction
Propagation of action potential in unmyelinated fibers. Is relatively slow and inefficient, especially for small diameter fibers.

Saltatory conduction
Propagation of action potential in myelinated fibers by jumping from node to node Myelin - a multilayered sheath of plasma membrane, derived from specialized glial cells, that wraps around axonal fibers and acts as an insulator to the flow of current (Figure 4-14; 4-15). The sheaths occur at regular intervals (~1mm), and are interrupted by gaps in the insulation called Nodes of Ranvier. The nodes contain high densities of voltage-gated Na+ and K+ channels and can generate action potentials. In myelinated axons, action potentials propagate by jumping from node to node through a process called saltatory conduction (Figure 4-16 in 5th edition only). This process greatly increases the speed of propagation. Schwann Cells - myelin-forming glial cells in the peripheral nervous system. Oligodendrocytes - myelin-forming glial cells in the central nervous system. Demyelinating Diseases - certain diseases, such as multiple sclerosis, result from the degeneration myelin.

Lecture 6: Synaptic Transmission I

Reading: chapter 4: synapses and neuronal integration, pgs 101-111 (pgs 117-128, if using 5th edition)

Synapses
Junction between two neurons, or between a neuron and a muscle or gland that enables one cell to electrically and/or biochemically influence another cell (Figure 4-15; 4-17). Synaptic transmission is the primary means of rapid inter-neuronal communication in the brain Presynaptic cell initiates the signal Postsynaptic (target) cell receives the signal Postsynaptic targets can be another neuron, a muscle or a gland

Electrical Synapse
A direct electrical connection between two cells, formed by a gap junction, that allows current to pass from one cell to another (Figure 3-6). Composed of multiple proteins called connexons. This type of synaptic connection has no delay and is less common than chemical synapses.

Chemical Synapse
Anatomical junction between two neurons, or between a neuron and a muscle or gland where a chemical neurotransmitter is released by the presynaptic neuron which diffuses across the synaptic cleft and binds to receptors on the postsynaptic neuron to exert a physiological response (Figure 4-16; 4-18). The presynaptic release of neurotransmitter, the postsynaptic response, and the removal of transmitter from the synaptic cleft are each governed by complex mechanisms.

Presynaptic release
Neurotransmitter is concentrated into synaptic vesicles in the presynaptic terminal, and is released through exocytosis when the vesicles fuse with the plasma membrane. Vesicle fusion depends on the presence Ca++ ions in the intracellular medium. Because the intracellular concentration of Ca++ is kept very low (on the order of 100nM), Ca++ must enter the synaptic terminal from the extracellular space. This occurs when an action potential propagates into the synaptic terminal and strongly depolarizes the membrane, causing voltage-gated Ca++ channels to open and allowing Ca++ to flow down its electrochemical gradient. The entry of Ca++ promotes the fusion of the vesicles with the plasma membrane and the neurotransmitter is released into the synaptic cleft. The opening of Ca++ channels in response to depolarization provides the mechanism that tightly links the release of transmitter to the occurrence of an action potential. At any given synapse there is usually, but not always, one type of neurotransmitter released.

Postsynaptic response
This response most commonly consists of a rapid and graded change in membrane potential in the postsynaptic neuron referred to as a post-synaptic-potential (PSP). PSPs occur when a neurotransmitter binds to a membrane protein called the postsynaptic receptor causing it to change its conformation and increase its permeability to one or more ions. For each type of neurotransmitter there is a distinct class of postsynaptic receptors. PSPs can exhibit a wide range of properties, but most commonly fall into two major categories (Figure 4-17; 4-19):

Excitatory-Post-Synaptic-Potentials (EPSP)
A depolarizing potential that tends to bring the cell towards threshold for generation of an action potential. These PSPs usually result from an increase in membrane permeability to a combination Na+ and K+ ions. The driving force pulling Na+ into the cell is greater than that pulling K+ out of the cell and the net result is depolarization. The most common excitatory neurotransmitters are glutamate (Glu) and acetylcholine (ACh).

Inhibitory-Post-Synaptic-Potentials (IPSP)
A hyperpolarizing potential that tends to bring the cell away from threshold for generation of an action potential. These PSPs usually result from an increase in membrane permeability to either K+ or Cl- ions. When the permeability to K+ is increased, K+ will flow out of the cell. When the permeability to Cl- is increased, Cl- will flow into the cell. In both cases, this leads to a hyperpolarization resulting from a net decrease in the amount of positive charge inside the cell. The most common inhibitory neurotransmitters are gamma-amino-butyric acid (GABA) and Glycine (Gly).

2nd messenger systems

Some neurotransmitters produce postsynaptic actions indirectly through the activation of intracellular second messengers. These are often referred to as neuromodulators. In these systems, the binding of neurotransmitter to the postsynaptic receptor triggers the enzymatic synthesis of molecules that can have widespread secondary actions. The type of 2nd messenger synthesized and its actions depend on the type of transmitter released and the class of postsynaptic receptor that is activated. A common 2nd messenger in neurons is cylic-adenosine-monophsphate (cAMP). Many transmitter types can lead to changes in the intracellular production of cAMP. Dopamine and serotonin are examples of neuromodulators.

Lecture 7: Synaptic Transmission II

Reading: same as Lecture 6 Transmitter removal
Several mechanisms are present in chemical synapses to remove transmitter that has been released into the synaptic cleft. The transmitter molecules can be degraded by enzymes present in the synaptic cleft, transported back into the presynaptic neuron by active transport, or can diffuse out of the cleft. Each of these mechanisms reduces the duration of action of the transmitter and insures that its action will be brief.

Examples of drug actions

Many drugs exert their actions on the nervous system by influencing one or more of the processes listed above. These actions are usually either antagonistic or facilitory. transmitter release - tetanus toxin blocks release of GABA transmitter uptake - cocaine blocks the reuptake of Dopamine - SSRIs (selective serotonin reuptake inhibitors such as Prozac, Zoloft or Paxil) block the reuptake of serotonin transmitter removal - many insecticides block the degradation of ACh transmitter binding - curare blocks the postsynaptic action of ACh at the neuromuscular junction - THC is an agonist for the endogenous cannabanoid receptor 2nd messenger pathway - caffeine enhances the action of cAMP at adrenergic synapses

Electrophysiological experiment at a synapse

1. Electrically stimulate a presynaptic axon. 2. Simultaneously record from a postsynaptic target neuron. 3. Perform experiment in the presence and absence of a chemical that blocks voltage-gated channels in the postsynaptic cell only. Results: With blocker? Without blocker? Without postsynaptic blocker but with ubiquitous blocker of voltage-gated Ca channels?

Synaptic Interactions and Neuronal Integration

Neuronal networks are wired together according to two simple anatomical principles (Figure 4-20; 4-22). A given neuron can receive thousands of synaptic inputs from many other neurons through convergence of these inputs. And the axonal connections of neurons can branch extensively so that they have a divergence of output. This type of connectivity means that most neurons receive thousands of synaptic inputs. They integrate this complex input using several simple physiological mechanisms (Figures 418, 4-19; 4-20, 4-21): convergence The synaptic input of many neurons on to one neuron divergence The synaptic output of one neuron onto many neurons temporal summation The additive effect of PSPs occurring close together in time spatial summation The additive effect of PSPs occurring together on nearby parts of the same cell presynaptic inhibition Synaptic inhibition of a synaptic terminal causing a decrease in transmitter release The ultimate outcome/goal of summation is to produce an action potential or train of action potentials in the postsynaptic cell, to carry on signaling to the next level of the neuronal network. The duration, rate and timing of action potentials in this output train encode information about the spatiotemporal pattern of converging inputs.