Physio Lecture 10 Dendrites

Don’t call a channel “closed”, call it inactive. A closed channel means something different.

Calcium is the electrical trigger that causes muscles to contract.

Physiology of a Neuron from Dendrite to synaptic transmission

Ligand gated channels tend to be proximal to the axon hillock (on the dendrites), and the voltage gated channels tend to be on distal to the axon hillock (on the axon)

Each neurotransmitter (NT) within a vesicle can excite or inhibit a neuron.

An inhibitory NT will hyperpolarize, making the inside of the cell more negative, taking it farther from threshold, so it is less likely to fire an action potential)

An excitatory substance will do the opposite; repolarize the membrane, make the inside of the cell more positive, bringing it closer to threshold, making it more likely to fire an action potential.

Function of Dendrites in Stimulating Neurons

•Dendrites spaced in all directions from neuronal soma.

–allows signal reception from a large spatial area providing the opportunity for summation of signals from many presynaptic neurons

•Dendrites transmit signals by graded local potentials from opening of LGC’s

•LGC (Ligand-gated channels): are not dependent on membrane potential but binding ofligands (e.g. neurotransmitters)

–Neurotransmitter receptors

–Located on dendrites and cell body

–Intensity of potential diffuses away from stimulus

There are ligand channels that let only sodium (Na) through. There are ligand channels that let only potassium (K) through. There are ligand channels that let only calcium (Ca) through. There are ligand channels that only let chloride (Cl) through. All of these ions are positively charged except chloride is negative.

Types of Ligand Gated Channels (LGC’s)

Pore loop: amino acids control which ions can pass

Gene Families- many different channel genes and have different structures, functions and expression patterns

Importance is found in diversity- many human diseases are associated with dysfunction of individual classes of ion channels

Na+ LGCK+ LGCChl- LGC

What would happen to the resting membrane potential if these channels opened?

If Na ligand channel opens, Na moves in, making the inside of the cell more positive, making it repolarized moving it closer to threshold for an action potential.

If K ligand channel opens, K moves out, making the inside of the cell more negative, making it hyperpolarized, moving it away from threshold for an action potential.

If Ca ligand channel opens, Ca moves in, making the inside of the cell more positive, making it repolarized moving it closer to threshold for an action potential.

If Cl ligand channel opens, Cl moves in, making the inside of the cell more negative, making it hyperpolarized, moving it away from threshold for an action potential.

Therefore, if K moves out or Cl moves in, the effect is inhibitory of an action potential.

If Na or Ca moves in, the effect is excitatory, and an action potential will fire if it is enough.

•The Excitatory Postsynaptic Potential (EPSP)is when the inside of a cell becomes more positive, such as when Na enters the cell. It is a graded potential, the exciting kind, brings it closer to threshold, less negative. How can we do that? Allow Na to get in.

•What if a neurotransmitter blocked the K leak channel?The inside of the cell would become more positive, moving closer to threshold (excitatory).Additional K would still move into the cell because of its concentration gradient is denser outside, so it would accumulate inside the cell. As the positive charges accumulate, it moves closer to threshold. The sympathetic nervous system will cause an increased heart rate. You will learn how it does this next week.

–Na+ ions rush to inside of membrane through ionophores opened by transmitter.

–The increase in voltage above the normal resting potential (to a less negative value is the excitatory postsynaptic potential.

–A single EPSP can be 0.5-1.0 mV (how many mV difference do we need to reach threshold?

•The Inhibitory Postsynaptic Potential (IPSP) is when the inside of a cell becomes more negative, less likely to reach its action potential.

–Inhibitory neurotransmitters open K+ or Cl- channels and causes hyperpolarization of the neuron. Making the neuron less likely to reach threshold

–Positively charged K+ ions moving to exterior make membrane potential more negative than normal (hyperpolarizing).

–Negatively charged Cl- ions moving to interior make membrane potential more negative than usual (hyperpolarizing).

People with Parkinson’s disease have a problem coordinating the excitatory and inhibitoryactions of their skeletal muscles. They have trouble starting and stopping any motion, and they shake at rest.

Top two inhibitory nerve transmitters: GABA and Glycine

They hyperpolarize the post synaptic neuron, less likely to fire an action potential.

Spatial summation is like when two people shouting at you: one says run, the other says stay.

Temporal summation is when one neuron is communicating to a cell over and over again.

Actually, there are hundreds of neuron synapsing on cells, so there is really a mixture of special and temporal.

A downstream neuron is receiving 100 different inputs at once (spatial summation).

If 75 of them were excitatory and 25 were inhibitory, the overall effect is excitement, less negative, so is closer to threshold.

Whether a neuron “responds” or not to a particular command depends on temporal and spatial summation of EPSPs and IPSPs.

These channels open and close rapidly providing a means for rapid activation or rapid inhibition of postsynaptic neurons.

1msec is needed for an action potential, but a graded potential can last ~15msec. This means we can “add” excitatory and inhibitory potentials

Temporal summation (above): same presynaptic neuron fires repeatedly

Spatial summation (below) - stimuli from two different presynaptic neurons (different locations)

The downstream neuron has to summarize the input. It is in constant flux up and down, until it reaches threshold. At threshold (voltage required to open Na channels first), they open barely, and rapidly, but the conductance of sodium into the cell increases 5000x. Because hundreds of thousands of Na channels are open, a graph produces an upstroke. If you take the ratio of Na over K, the Na during the upstroke will be a large number, so the ratio is a large number. Towards the peak of AP (the peak of the upstroke on the graph), the conductance for Na starts to decrease, channels are inactivating. Then K channels are opening during the downstroke, the inside of the cell becomes more negative. At this point, the ratio of Na/K is a smaller number because there are few Na channels open and many K channels open.

Disturbing an Excitable Cell

•Electrical stimulation (or even mechanical stimulation) can result in changes in voltage. Depolarizing currents change the voltage on the membrane, bringing it toward threshold:

–If stimuli are sub-threshold, the result is a local potential

–If stimuli are threshold or above threshold stimuli, the result is an action potential

What happens at threshold?

•A temporary, short-lived membrane permeability change. Membrane becomes 40 x more permeable to Na+ than to K+, then quickly returns to previous state

•How?

•Opening and closing of voltage-gated channels. VGC (Voltage-gated channels): Open/close depending on the voltage across the membrane

–Na+ VGC, K+ VGC, Ca++VGC

–These VGC’s are located on the axon, at hillock and distal to it

•Can allow ions to move at high rates

•Allow ions to move down their EC gradients

•Conductances are voltage dependent

•Threshold is the “trigger” that starts a “dance of the gates”

On the above graph, you can take a ratio of red to blue: red is Na permeability, blue is K permeability.

On the upstroke, this ratio is a large number. It becomes smaller on the downstroke.

Larger number reflects the Na coming into the cell, making inside of the cell more positive.

Smaller number reflects the K leaving the cell, making the cell more negative. When it becomes more negative than it started at, it is hyperpolarized, so all the K channels close, allowing ATPas to clean up the particles on both sides of the membrane.

Resting membrane potential is negative because of three things:

Proteins are negatively charged, and there are many inside cell

Na is outside with its positive charge

K leaks out, taking its positive charge with it

The action potential, dance of the gates

•Upstroke

–Na+ permeability increases

–Membrane potential approaches E Na+

•Downstroke

–Potassium permeability increases

–Hyperpolarization occurs due to increased K+ conductance from late K+VGC closure

–Membrane potential approaches E K+

Functions of action potentials

•Information delivery to CNS

Transfers all sensory input to CNS.

The frequency of APs encodes information (recall amplitude cannot change).

•Rapid transmission over distance (nerve cell APs)

Note: speed depends on fiber size and whether it is myelinated.

In non-nervous tissue APs are the initiators of a range of cellular responses.

Muscle contraction

Absolute refractory period (ARP)

As soon Na channels open, the absolute refractory period begins. As the inside of the cell becomes more positive, the ball and chain portion of the ligand gated channel becomes more positive, causing the ball and chain to move, occluding the channel, blocking it.When a red traffic light turns green, it is on a timer; you can’t make it change faster. At the end of the timer, it will turn yellow. As Na enters the cell, it makes the area more positive, and the channels cannot stay open because of the ball and chain. To get them to reopen, you have to make them more negative so the external portion of the gate will reset so it can open.

The Absolute Refractory Period is an indication of the Na VGC gating status.

The Na VGC’s have three gating actions: active, inactive, and deactive.

There is no conductance when the gate is inactive or deactive.

Active and inactive are part of the Absolute Refractory Period.

When it is deactive, no Na going through, but if inside of cell voltage changed, it could become active again.

Relative Refractory period (RRP)

During this phase, the threshold is higher, so you need a greater stimulus to open the channel again.

ION CHANNELS – ACTIVATION, INACTIVATION, DEACTIVATION

•Depolarization causes:

Na channels to activate (open)

But it also causes inactivation

inactivated channels do not pass any ions (non-conducting state)

By contrast, most K channels show activation and deactivation but not inactivation

•The fall in current at the end is deactivation (opposite of activation)

If the Na channels are becoming inactive, no action potential can fire. This is the peak of the absolute RP; no stimulus will trigger another AP. But give it enough time, and a second AP can be generated in quick succession to the first.

Action Potentials allow neurons to convey info to CNS rapidly and frequently. Can fire hundreds of thousands of times without depleting the Na gradient.

The larger the neuron, the less resistance there is. The more lanes on the freeway, the faster you get home.

A neuron with myelin saves on ATP. Myelin cells (Schwann cells or oligodendrocytes) wrap themselves around the axon of a neuron, leaving bare areas called Nodes of Ranvier.You don’t need to have a Na VGC all the way down the axon. They occur in clusters at the Nodes of Ranvier.

Functions of action potentials

•Information delivery to CNS

  • Transfers all sensory input to CNS.
  • The frequency of APs encodes information (recall amplitude cannot change).

•Rapid transmission over distance (nerve cell APs)

  • Note: speed depends on fiber size and whether it is myelinated.
  • Saltatory Conduction
  • AP’s only occur at the nodes (Na channels concentrated here!)
  • increased velocity
  • energy conservation
  • In non-nervous tissue APs are the initiators of a range of cellular responses.
  • Muscle contraction

Myelin is a support cell that wraps itself around the neuron many times. Unmyelainated neurons have support cells too, but the support cells are not wrapped around them, they just tether them in place.

For example, when you take a piece of gum and pick up a mint, the mint is like an unmyleinated axon and the gum is like the support cell thatsupports the mint but does not wrap around it.

When you roll up your tube of toothpaste, a thin layer of paste will still be inside the tube at the end where you are rolling. The aluminum of the tube is like the phospholipid bilayer of the myelin cell. The two sides of the cell membrane get closer together, and all of the cytoplasmic contents get squished out toward one end of the cell. These layers of cell membrane increasethe conductivity of the neuron.

When the electrical current is detected between the myelin rolls, the left side of the sheath conducts the impulse immediately to the right side of the myelin cell.A child under three should not be on a low fat diet because a lot of their myelin is being made during that time.

MS is auto immune attack of the myelin sheaths. The symptoms are gradual and vague, and by the time they get to a doctor, much damage has been done. There are treatments, but no cure. The person suffers from progressive muscle weakness, from distal to proximal, until the diaphragm becomes weakened, and they can no longer breathe. They still feel pain; they just lose motor function of the muscles. Women are twice as likely to get MS as men. Women tend to have a higher level of a protein called interferon gamma, which promotes inflammation within the nervous system.

Ion channels – Activation, Inactivation, deactivation

•Depolarization causes:

Na channels to activate (open)

But it also causes inactivation

inactivated channels do not pass any ions (non-conducting state)

By contrast, most K channels show activation and deactivation but not inactivation

The fall in current at the end is deactivation (opposite of activation)

Need calcium ATPase to push the calcium out, but some can be sequestered.

Calcium is the ion that drives exocytosis of neurotransmitters (causes NT to be released).

The Synapse

•Structures important to the function of the synapse:

–presynaptic vesicles

•contain neurotransmitter substances to excite or inhibit postsynaptic neuron

–mitochondria

•provide energy to synthesize neurotransmitter

•Membrane depolarization by an action potential causes emptying of a small number of vesicles into the synaptic cleft

•Presynaptic membranes contain voltage - gated calcium channels.

–depolarization of the presynaptic membrane by an action potential opens Ca2+ channels

–influx of Ca2+ induces the release of the neurotransmitter substance

•Postsynaptic membrane contains receptor proteins for the transmitter released from the presynaptic terminal.

Synaptic Events

•NTS release

•NTS diffuses across cleft

•Binds to receptors (LGC’s) reversible binding

•Opens LGC (LGC’s are ion selective) and diffusion of ions: Influx or efflux

•Allowing depolarization or hyperpolarization of cell body

•Result in graded voltage changes, local potentials in postsynaptic cell body

•If depolarizing, called EPSP

•If hyperpolarizing, called IPSP