Physiology Exam 2

membrane-spanning

enzymes

receptors

structural proteins

carrier proteins

saturated

chemically gated channels, voltage-gated channels, mechanically gated channels

gated

3 Na+, out of, 2 K+, into

electrogenic

aquaporins

open or leak

plasma and interstitial fluid

circulatory system

specificity

resting membrane potential

-70

67% is intracellular. 33% is extracellular; of that 75% is in the interstitial fluid and 25% is in the plasma.

Transport epithelia have cells that are polarized with respect to distribution of transport proteins in the apical and basolateral membranes, i.e., different types of transporters in the two membranes. Nerve cells are electrically polarized, meaning that the inside of the membrane is charged relative to the outside.

This statement is only partially true. The two compartments have stable solute compositions, but they are not in equilibrium. We use the term dynamic disequilibrium to describe this relationship

Osmotic equilibrium occurs because water moves freely between most cells and the extracellular fluid. Water will continue to move across membranes into more highly concentrated compartments until the concentrations (solute/volume) are equal, hence osmotic equilibrium. Osmotic equilibrium does not take into account what particles are present in each compartment, just the total number. The key is that water moves freely, but the solutes do not. Na+ and Cl- are more highly concentrated in the ECF while K+ and many anions are more highly concentrated inside the cell. Each ion is in chemical disequilibrium because it is not evenly distributed between the two compartments. Although the compartments are chemically different (chemical disequilibrium), when all solutes in one compartment are compared to all the solutes in another compartment they have the same total concentrations of solutes (are in osmotic equilibrium).

The phospholipid bilayer is a fluid mosaic and, depending on the function of the cell, contains various ratios of phospholipids, cholesterol, and proteins. Water molecules slip between the spaces between the fatty acid tails. Membranes with higher levels of cholesterol are less permeable to water because cholesterol fills these spaces.

Most polar molecules must be assisted by a protein, because the molecule will not interact with the nonpolar phospholipid tails. Examples are facilitated diffusion and active transport. Because water is very small and electrically neutral, it is able to diffuse between the phospholipid tails.

Water can cross through the phospholipid molecules, through special water channels called aquaporins, and through open or leak channels (pores) that also transport ions. Water can move through pores as a solvation shell around ions or independent of ions, because the watery interstitial fluid is continuous with the watery cytosol when pores are open. Some cells are more permeable to water, especially those with less cholesterol in the membranes and those with a high density of pores.

Channel proteins allow more rapid transport, but are not as selective. Carrier proteins are slower because of the conformation change. They are also more selective and can move larger molecules than channel proteins. Carrier proteins never allow free exchange across the membrane because they never create a continuous passage between the inside and outside of the cell.

Fick's law of diffusion determines the rate of diffusion. The flux of a molecule is the rate of diffusion per unit surface area of membrane. Fick's: Rate of diffusion = concentration gradient × membrane permeability × surface area Flux = concentration gradient × membrane permeability

1. the diameter of the central pore 2. the electrical charge of the amino acids that line the channel

Both involve binding of substrate to a carrier, but facilitated is passive, moving solutes down their concentration gradients, whereas active requires ATP and can move solutes against their concentration gradients.

All forms of transport require energy, because something is being moved. A. Passive transport uses the thermal energy present in the living cell to move molecules in the energetically favorable downhill direction (with concentration gradients). B. Active transport uses the energy transferred by the ATP molecule, to move molecules in the energetically unfavorable uphill direction (against concentration gradients). C. Vesicular transport uses the energy of the ATP molecule also, to move large molecules or large quantities of molecules.

Cotransport is the moving of more than one kind of molecule at one time. Antiport is cotransport of two or more solutes in opposite directions across the membrane. Symport is cotransport of two or more solutes in the same direction across the membrane.

Both ultimately depend on the energy of ATP, but dependence is indirect in secondary, direct in primary.

Secondary active transport uses the energy released from moving one molecule down its concentration gradient to push other molecules against their concentration gradient. ATP is used to create the chemical disequilibrium (or concentration gradient) for the first molecule.

Dynamic indicates that materials are constantly moving from compartment to compartment, but steady state implies there is no NET movement between the compartments.

1. connect membrane to the cytoskeleton to maintain cell shape 2. create cell junctions that hold tissues together 3. attach cells to the extracellular matrix by linking cytoskeleton fibers to extracellular collagen and other protein fibers

Higher concentrations of cholesterol in the cell membrane reduce membrane permeability to water.

See Table 5.4 in the chapter.

A. Chemical reaction equilibrium is achieved in reversible reactions when the rate of the forward reaction equals the rate of the reverse reaction. At this state there is no net change in the concentration of reactants and products in the system. This does not mean that concentrations are equal. B. Chemical equilibrium occurs when the concentration of a particular solute in one location equals that in another. Typically the locations compared are intracellular vs. extracellular. C. Osmotic equilibrium occurs when total solute concentration is the same, though chemical disequilibrium may exist.

A fluid is a substance that flows. Bulk flow is movement of a fluid, usually within a body compartment. Liquids and gases are fluids, and they flow. Gases are compressible, but liquids are not.

Mechanically gated (in sensory cell receptor potentials), voltage-gated (in nerve and muscle action potentials), and chemically gated (in neuromuscular synaptic transmission).

Controlled variables may include temperature, pH, composition and volume of solvent or medium, amount of solute added. Solutes could be soluble dyes of different molecular weight, and rate of diffusion could be estimated by observing the extent of coloration around a dye crystal at specified intervals.

Kidney cells may have fewer open channels through which water can pass, and/or they may have more cholesterol in their membranes.

Molarity is the number of molecules per liter of solution, while osmolarity is the number of independent particles per liter. The ionization of salt in water illustrates the importance of this distinction: one mole of sodium chloride dissociates to produce a total of two moles of particles (one mole Na+ and one mole Cl-), or two osmoles. Osmosis is diffusion of water. A one molar solution of sodium chloride (two osmolar) produces higher osmotic pressure than a one molar solution of glucose, which does not dissociate.

Osmolarity refers to the concentration of individual particles in solution. Tonicity refers to the behavior of a cell in a solution. They are similar in that both are related to particles in solution. They are different in that osmolarity depends only on the total concentration of particles in solution, whereas tonicity depends on nature of the particles (i.e., are they penetrating or nonpenetrating) as well as on the concentration of the different particles.

See Figure 5.26b in the chapter.

Because the kidney is failing to filter particles out of the blood effectively, the plasma becomes hypertonic or hyperosmotic in comparison to the intracellular compartment of the blood cell. Since the cell membrane is impermeable to the ions, but permeable to water, water will leave the cell to try to balance the tonicity and osmolarity with the plasma and in the process the cell will shrink.

The transport maximum occurs when all carrier binding sites are filled with substrate. At this point adding more substrate will no longer increase the rate of transport. In order to increase the capacity and raise the maximum rate of transport, some cells can increase the number of carrier proteins in the membrane.

Low concentrations of potassium in the blood is a condition called hypokalemia. Interstitial fluids would similarly become low in K+. As the resting potential of nerve and muscle cells depends primarily on extracellular K+ concentration, the potential would be altered. Decreased extracellular K+ would increase the concentration gradient for movement of K+ out of the cells, which would gradually hyperpolarize the potential as positive ions exit and make the cells less excitable (farther from threshold).

Potassium is a cation that leaves the cell during an action potential or depolarization of a muscle or nerve cell, and the muscle or nerve cell needs to move potassium back into the cell to allow the cell to repolarize and relax. If there is a deficiency in potassium, muscle and nerve cells may take longer to repolarize and therefore relax, so increasing your dietary intake of potassium may help cells repolarize quicker.

Active transport of chloride is impaired, in the airways, sweat glands, and pancreas. The affected epithelia are involved in production of sweat and mucus. Thus, the respiratory, integumentary, and digestive systems are affected. Treatments include replacement of pancreatic digestive enzymes, which are blocked from secretion by the mucus buildup in secretory ducts, and respiratory therapies to loosen mucus in the airways and treat recurring infections. Gene therapy is being explored as well. Median survival is 37 years as of the publication date of the textbook. Causes of death can be related to malnutrition and respiratory illness. This is a genetic disease, in which the gene coding for the chloride transporter is abnormal.

ATP dependent potassium gates keep the insulin releasing channels closed when there is enough glucose getting into the cell. When glucose levels drop and the amount of ATP the beta cell is making drops, it eventually loses the energy to keep the gates closed, therefore opening and allowing insulin to be released into the blood.

targets

nitric oxide, carbon monoxide, hydrogen sulfide

endothelial cells (blood vessel lining), endothelial-derived relaxing factor (EDRF)

diseases

eicosanoids, sphingolipids

Signal transduction, first messenger, second messenger

connexins

paracrine

autocrine

neurocrines

antagonists

up-regulation

Internal Environment

G-proteins

protein kinases

Epinephrine can bind to different isoforms of the adrenergic receptor. Epinephrine binds to the alpha receptor on the intestinal blood vessels and beta receptors on the skeletal muscle blood vessels (see Fig. 6.14).

homeostasis

nervous, endocrine

second messenger

simple endocrine

receptor, effector

constrict, dilate

: The cells can: 1. transfer signal molecules to adjacent cells through gap junctions 2. use contact-dependent signals, which rely on interactions between cell surface molecules on different cells 3. use locally acting chemicals, called paracrines, autocrines, or neuromodulators 4. use long-distance means, which rely on combinations of electrical and chemical signals

Either the number of receptors decreases or desensitization in which the binding affinity of the receptors for the ligand decreases. In both cases the result is a lessened response of the target cell even though the concentration of the signal molecule remains high.

the time required for a signal to lose half its activity

a receptor that has no known ligand

tonic control

The two types of cells differ either in the receptors on their cell membranes or in the signal transduction that occurs after binding of insulin.

Ligand-gated receptors are ion channels, integrins are linked to the cytoskeleton, receptor-enzymes activate intracellular enzymes, G protein-coupled receptors involve activation of G proteins. See Figure 6.3.

These drugs act on membrane receptor proteins.

Leukotrienes are secreted by certain types of white blood cells and play a role in asthma and anaphylaxis. Prostanoids, including prostaglandins and thromboxanes, have a variety of target tissues and effects.

See Figure 6.4 and the "Membrane Proteins Facilitate Signal Transduction" section in the chapter.

Nonsteroidal anti-inflammatory drugs, such as aspirin and ibuprofen, prevent inflammation. They have side effects such as bleeding in the stomach.

Tonic control regulates physiological parameters in an up-down fashion. An example is the neural regulation of blood vessel diameter (see Fig. 6.15).

See Figure 6.1 and the "Long-Distance Communication May Be Electrical or Chemical" section in the chapter.

Insulin promotes glucose transport into most types of cells. Diabetes mellitus results when insulin regulation of blood glucose concentrations is impaired. In type I, the pancreas fails to produce insulin, whereas in type II insulin levels are normal to high, but target cells fail to respond properly. Insulin injections can successfully treat type I, but not type II, because the endogenous insulin production in type II is sufficient, but the response is abnormal.

G proteins are coupled to hundreds of different receptors on cells. These are receptors that bind ligands such as hormones, neurotransmitters, and molecules important in sensory systems. Activated G proteins open ion channels or alter enzyme activity. The G protein-coupled adenylyl cyclase-cAMP system was the first signal transduction pathway discovered, and therefore paved the way for our understanding of signal transduction. cAMP is the second messenger in many signaling systems. Nitric oxide functions as a neurotransmitter, neuromodulator, and paracrine important in cardiovascular regulation.

When sulfur compounds are metabolized, hydrogen sulfide may be produced. This gas has recently been shown to be a signal molecule that relaxes blood vessels.

Carbon monoxide is one of the gaseous signal molecules. It activates guanylyl cyclase and cGMP in smooth muscle and neural tissue

Receptor molecules are proteins on or in cells that bind to ligands. This binding triggers a response within a cell, to the signaling chemical. For example, this is how a hormone exerts its effect on a target cell. Receptors in a reflex arc are not protein molecules but rather are entire cells, parts of cells, or multicellular structures. These receptors cause a signal to be sent to an integrating center, which may or may not then initiate a response usually involving many cells. For example, a blood pressure receptor detects a decrease in pressure, and sends a neural signal to cardiovascular integrating centers to trigger a vascular response to increase pressure.

Stimulus: increased blood glucose. Integrating center: endocrine cell (in pancreas). Efferent pathway: insulin secretion. Response: increased cellular uptake of glucose. Feedback: negative. Stimulus: decreased blood glucose. Integrating center: endocrine cell (in pancreas). Efferent pathway: glucagon secretion. Response: release of glucose from cells. Feedback: negative.

Brain cells lack the insulin receptors that stimulate glucose uptake, because an insulin-independent mechanism for glucose uptake is present. Brain cells will down-regulate their glucose transporters during periods of hyperglycemia. When insulin levels increase during treatment of type I diabetes, promoting lower concentrations of glucose in the blood, this can trigger diabetic coma because the brain cells have too few glucose transporters for the new, lower levels of blood glucose.

nodes of Ranvier

voltage

driving force

graded potentials and action potentials

threshold

all or none

absolute refractory period

relative refractory period

chemical

electrical

neuromodulator

temporal summation

spatial summation

1. the concentration gradients of ions across the membrane 2. the membrane permeability to those ions

False, peripheral nervous system

False, nodes of Ranvier

true

true

true

False, temporal summation

(anterograde) axoplasmic transport

retrograde transport

membrane potential

excitatory

inhibitory

summation

summation

metabotropic

Answers will vary. There are three divisions: the central nervous system (CNS), the peripheral nervous system (PNS), and the enteric nervous system. The CNS consists of the brain and spinal cord and acts as the integrating center for neural reflexes. The brain is also where thoughts and consciousness are formed. The PNS includes the afferent branch, which monitors the internal and external environment and sends signals to the CNS, and the efferent branch, which carries signals from the CNS to effector cells throughout the body. Within the efferent branch, there is the somatic motor division, which controls skeletal muscle, and the autonomic division. The autonomic division, or visceral nervous system, controls the smooth and cardiac muscles and exo- and endocrine glands. It is further divided into the sympathetic and parasympathetic branches.

Energy is required in order to move synaptic vesicles to the cell membrane.

The organelles and cellular components transported to the axon terminal must also be returned to the cell body for recycling. Fast retrograde recycling may also be used for nerve growth factor transport to the cell body

Action potentials are stereotyped changes in axon membrane potential that function in long-distance communication between neurons and their target cells. Graded potentials are variable membrane potential changes, usually in dendrites of multipolar neurons, that function in either short-distance communication or changing the probability of an action potential. Action potentials result from opening of voltage-regulated ion channels, which occurs at or above a threshold voltage. Graded potentials are not regenerative and result from the opening of ion channels in response to neurotransmitter or a specific stimulus such as sound or odor, in the case of sensory receptors. The rising phase results from influx of sodium, and the falling phase from efflux of potassium. Other characteristics include the after-hyperpolarization, all-or-none nature, conduction without decrement, independence of amplitude and duration from stimulus strength, refractory period, faster velocity in larger diameter or in myelinated axons. Graded potentials can be depolarizing, if the ion channel is a sodium channel, or hyperpolarizing in the case of potassium or chloride channels. Depolarizations increase the probability that threshold voltage will be attained and an action potential will result. Hyperpolarizations decrease the probability of a resulting action potential. Amplitude and duration are proportional to stimulus intensity, and graded potentials are conducted with decrement.

Fast synaptic potentials begin quickly and last only a few milliseconds; this category includes EPSPs and IPSPs. Slow synaptic potentials take longer to begin and last longer commonly involve G-protein coupled receptors; this type of response is important in growth, development, and long-term memory.

Dendritic spines have polyribosomes to make their own proteins, send signals to other neurons, and are involved in learning, memory, and various pathologies. PNS dendrites receive external information and transfer it within the neuron.

Both insulate axons by creating myelin. Schwann cells, found in the PNS, are associated with a single axon. One axon may have many Schwann cells wrapped around it leaving small gaps of unmyelinated areas called nodes of Ranvier. Oligodendrocytes are found in the CNS and form myelin around portions of several axons.

This is discussed in the "Electrical Signals in Neurons" section of the chapter. The Nernst equation is used to calculate the equilibrium potential for individual ions, while the GHK equation calculates the predicted resting membrane potential of a cell. The equilibrium potential is the voltage at which there is no net movement of a particular ion across the membrane, because the force of the concentration gradient is exactly balanced by the force of the electrical gradient.

Current leakage across the membrane and resistance of the cytoplasm are two factors.

1. opens or closes existing channels 2. inserts or removes membrane channels

Although both channels are activated by depolarization, the Na+ channels open quickly allowing rapid Na+ entry into the cell. The peak of Na+ permeability coincides with the peak of the action potential, while the K+ channels open more slowly and don't reach their peak ion permeability until the falling phase of the action potential.

The trigger zone is an area of the neuron that contains a high membrane concentration of voltage-gated Na+ channels and is near an area that lacks these. In order for action potentials to occur, graded potentials reaching the trigger zone must depolarize the membrane to the threshold voltage. In efferent and interneurons, the trigger zone is the axon hillock (also called the initial segment). In afferent neurons, the trigger zone is located where the dendrites join the axon (immediately adjacent to the receptor), rather than at the axon hillock. The axon hillock is an anatomical region, whereas the trigger zone is defined by its function rather than its location.

False. The refractory period occurs after action potentials and is a distinguishing characteristic, and results from properties of the voltage-gated sodium channels. Graded potentials do not involve channels that have refractory periods. Two stimuli that reach a dendrite at nearly the same time will increase the graded potential produced, whereas if two suprathreshold depolarizations reach the trigger zone at nearly the same time, the first will cause an action potential and the second will be ignored, because of the refractory period.

During the relative refractory period, a smaller than normal action potential can occur. During this period potassium channels are still open causing repolarization. If a wave of depolarization occurs, Na+ can enter the cells through the newly reopened Na+ channels, but this depolarization is offset by the K+ efflux.

With the kiss-and-run model the synaptic vesicles fuse to the presynaptic membrane at a fusion complex. When the neurotransmitter is released through the fusion complex into the synaptic cleft the vesicles then pull away from the complex and re-enter the vesicle pool in the cytoplasm. With the classical model the vesicle becomes incorporated into or becomes part of the cell membrane.

The average resting membrane potential is -70 mV. It is primarily determined by the concentration gradient of K+ and the membrane permeabilities of K+, Na+, and Cl-. The equilibrium potential for K+ predicted by the Nernst equation is -90 mV. The resting membrane potential is more permeable to K than Na. However, because the cell's resting potential is more positive than -90mV there must be another contributing ion, and it is the Na+ leak channels that allow positive Na+ ions into the cell which cause the resting potential to be slightly more positive.

Assuming sodium channels are functioning normally, there would still be an action potential. Threshold would be unaffected, because it is a property of sodium channels. A peak voltage will be reached when the sodium channels become inactivated; this voltage may be higher than normal since usually there is a partial canceling of the rising voltage as potassium exits. Without a potassium current, the falling phase would be much slower, being dependent on the sodium-potassium pump removing the sodium ions that came in. The undershoot would be absent because it is a result of potassium current.

The channels have two gates: activation and inactivation gates. (See Fig. 8.10.) At rest, the activation gate is closed and the inactivation gate is open. Upon depolarization both gates move: the activation gate opens allowing Na+ to enter the cell and the inactivation gate (with a delay of 0.5 msec) closes stopping the influx of Na+. At this point during the action potential, the peak has been reached and repolarization occurs due to the K+ ions leaving the cell. During this time, even if another wave of depolarization occurred, the Na+ channels cannot be opened because the activation gate is already open and the inactivation gate is closed. This is the absolute refractory period, when another action potential absolutely cannot occur because the Na+ channels have not reset to their original positions. The relative refractory period occurs after some of the Na+ channels have reset, but a higher than normal depolarizing graded potential is necessary to cause another action potential. Refractory periods also explain why action potentials cannot move backward. (See Fig. 8.15.) The part of the axon experiencing the action potential has open Na+ channels. An increase in Na+ inside the cell causes depolarization and perpetuates the action potential toward the axon terminal due to local current flow. The area of the axon toward the trigger zone, where the action potential (AP) occurred a moment earlier, is in the absolute refractory period and will not experience another action potential even with a depolarization.

As a depolarization wave moves through the cell, some of the positive charge is lost to the extracellular fluid through leak channels. Additionally there is cytoplasmic resistance. Action potentials do not lose strength because they are regenerated in each patch of membrane.

EPSPs and IPSPs are graded potentials in postsynaptic cells resulting from the action of neurotransmitters at synapses, which are usually on dendrites of multipolar neurons, but could also be on the synaptic region of any target cell. EPSPs increase the probability that a postsynaptic action potential will result, because they involve an influx of sodium, which depolarizes the membrane potential, bringing it closer to threshold. IPSPs decrease the probability that a postsynaptic action potential will result, because they involve either an influx of chloride or an efflux of potassium, either of which hyperpolarizes the membrane potential, moving it farther from threshold. Action potentials occur in axons of neurons, or in muscle cell membranes. They may result from PSPs or in the case of sensory neurons, specific stimuli such as sound or odor, which cause a type of graded potential called a receptor potential. Action potentials begin when graded potentials depolarize the membrane potential to threshold. The rising phase of an action potential results from sodium influx, and the falling phase from potassium efflux. Action potentials, but not graded potentials, are an all-or-none phenomenon.

See Figs. 8.24 and 8.25 in the chapter. Temporal summation is the addition of graded potentials that overlap in time; that is, a second potential arrives before the first one from that source has finished. Spatial summation occurs when there is simultaneous arrival of graded potentials originating from more than one synaptic input. Summation occurs at the trigger zone. Typically a multipolar neuron has many active synapses at a given time, with multiple potentials being produced at each. Summation demonstrates postsynaptic integration.

A nerve consists of many axons. A regular action potential is produced by a single axon, whereas a compound action potential is recorded by equipment from a nerve when multiple axons are producing action potentials, and the voltages add together. Increasing stimulus intensity increases the number of axons contributing to the compound action potential. This is because different axons have different threshold voltages, so increasing the voltage stimulates a larger number of axons.

Action potential arrives in synaptic terminal, and stimulates opening of voltage-regulated calcium channels. The resulting calcium influx triggers exocytosis of synaptic vesicle contents. The phospholipids of the vesicle membranes are recycled, either from fusion of vesicles then later formation of new vesicles from the same molecules; or from the kiss-and-run model, in which the vesicle phospholipids are not incorporated into the membrane at all, but remain as vesicles that can be refilled with neurotransmitter.

Synaptic plasticity is the changeability of synapses, necessary for development and continued learning in the nervous system. Neuroglia play an important role in healing of damaged neural tissue. Schwann cells in the PNS facilitate regrowth of severed axons. CNS glia seal off and scar a damaged region. Neurotrophic factors are important in maintaining active synapses.

Maximum frequency is mostly dependent upon the duration of the absolute refractory period, which determines the upper limit. The diameter of the axon, amount of myelination present, and the magnitude of the Na+ and K+ gradients across the axonal membrane all affect action potential velocity may also play a secondary role.

Neurotransmitters usually do not enter the cell, thus must combine with receptors on the membrane, using mechanisms similar to the amino acid-derivative hormones. Similarities include opening channels in the postsynaptic cell membrane, leading to depolarization of the neuron. In endocrine target cells, the arrival of the stimulus begins a different sequence of events, such as triggering an enzyme cascade, and second messenger systems.

Schwann cells, present in the PNS but not the CNS, facilitate regrowth of severed axons. This means that people do not recover as well from CNS injury compared to PNS injury. It is possible that there is something fundamentally different in CNS axons compared to PNS axons that accounts for this effect. To test for this, Schwann cells could be transplanted into the spinal cord or brain and CNS axons observed for regrowth. Such experiments have been done, and it is the case that CNS axons are capable of regrowth in the presence of Schwann cells. Identification of chemical or physical factors in the Schwann cells would advance this field of research.

8.9

: EK+ = 61 log 150/5 = 90.10 mV, ENa+ = 61 log 175/15 = 65.08 mV, ECl- = -61 log 40/40 = 0 m [ ] in mOsm/L Cell Swamp K+ 5 150 Na+ 15 175 Cl- 40 40

X AP/2 msec × 1000 msec/1 sec = 500 APs per second.

It would be appropriate for the student to draw action potentials on the graph beginning at the point where the resting potential drifts up to threshold, and decreasing in frequency as the resting potential approaches. Very gradually, a cell's resting membrane potential would increase until it reached and stabilized there. At that point the ions would be in equilibrium, and no further net flow of charge would occur. There would be no effect on ability to generate action potentials INITIALLY, but with the disappearance of the differential distribution of sodium and potassium upon which the action potential depends, action potentials would gradually come to a stop. This points out the fact that during any SINGLE action potential, so few ions cross the membrane that there is no significant change in ion concentrations. Thousands of action potentials would be required before the absence of the sodium-potassium pumps would be noticeable.

Both AMPA and NMDA receptors are located on the postsynaptic cells (dendrites) and require binding of the excitatory neurotransmitter glutamate for activation. When glutamate binds to the AMPA receptor, the channel opens and Na enters the cell. This causes depolarization of the immediate postsynaptic cell or dendrite. This depolarization causes Mg2+ ions to be "kicked out" of the NMDA receptor channel; hence, Mg2+ is no longer acting as a channel blocker. If at the same time glutamate is bound to the NMDA receptor then the channel gate is open and Ca2+ enters the cell. The entry of Ca2+ triggers 2nd messenger pathways that result in an increase in the number of glutamate receptors inserted into the post-synaptic membrane. This increases the probability of an increase in the postsynaptic response or depolarization to glutamate that is referred to as long-term potentiation.