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Introduction

  • Physiology – the study of body function
  • Body/behaviour --> Organ/sytems --> Cell physiology --> Molecular
  • Luigi Galvani came up with the idea of “animal electricity”
    • Hanging frogs legs on a metal rod
    • Ligning bolt caused muscles to contract
    • Didn’t understand the observations

The action potential

Action potential
  • The action potential is a unit of electrical signalling in excitable cells
  • In a single neurone, there is about 100 mV response for ~ 1 ms
  • We use patch-clamp recording of action potentials (nerve impulses)
    • Glass electrode with dye to stain the neurone
    • Dye shows the complex morphology of a neurone in the cortex of a rat brain

Cells use electrical signals to function – “excitable cells”

  1. Neurones respond to sensory stimulus with an electrical signal and use electrical signals to communicate with each other and with the tissues they control
    • Clinical implications:
      • Diseases such as epilepsy (altered firing/excitability), anxiety, many others
      • Drugs such as sedatives (valium etc), alcohol and many other used and abused drugs
  2. Cardiac, skeletal and smooth muscle cells
    • Action potentials cause muscle cells to contract (smooth muscle includes peristalsis etc)
    • Clinical implications:
      • Diseases: Arrythmia, tachycardia, paralysis, gut spasms, altered blood pressure
      • Drugs: Anti-arrythmia, anti-hypertensives, muscle relaxants
  3. Secretary and absorbing epithelial cells
    • E.g. glands, kidney, lungs, gastro-intestinal tract
    • Ion gradients and membrane transport proteins are needed to move substances between locations
    • Clinical implications:
      • Diseases: diarrhoea, cystic fibrosis, renal disease, saliva, metabolic disorders
      • Drugs: anti-diabetics, diuretics, many others
    • Ion transport is used in the lung to pass water across the membrane
    • Cystic fibrosis (a genetic disorder) affects epithelial cells in the body (e.g. the lungs)
      • In the lungs, this causes thick mucus to build up
      • The mucus becomes infected (microbes clog it up)
      • Causes death

The membrane potential

  • Membrane potential (Vm) is the voltage difference between the inside of a cell and the outside (the outside is the zero/ground)
    • About -70 mV normally
  • Changes in Vm:
    • Depolarisation: Vm becomes more positive (less negative) e.g. from -70 mV to -60 mV
    • Hyperpolarisation: Vm becomes less positive (more negative) e.g. from -70 mV to -80 mV
    • Repolarisation: Vm returns to the resting value following a depolarisation (a special type of hyperpolarisation)
  • An action potential is a change in the membrane potential
    • All cells have different ion concentrations on the inside and the outside of their membranes
    • Ion transporters maintain the membrane voltage
    • Change in ion concentration via the transporters causes de/hyperpolarisation
  • Threshold of excitation: enough depolarisation to start an action potential

Voltage thresholds and action potentials

  • Certain stimuli cause some change in Vm
  • If Vm is changed in the positive direction (depolarised) to a certain “voltage threshold”, then this causes an action potential
  • To get to the threshold, there are a number of possible stimuli:
    • Pacemaker activity (spontaneous Vm changes – self-stimulating) e.g. the heart doesn’t need external stimulation
    • Synaptic responses
    • Sensory stimulation (e.g. when he clapped his hands we all looked up)
    • Abhorrent nerve activity (epilepsy, arrhythmia)
      • AP’s where we don’t want them

Physio2-3.png Referring to the diagram:

  • We are looking at experimental injections of current to the system
  • If the depolarisation stimulus is below the threshold, we only get a small response
  • If the depolarisation stimulus is above the threshold, we get a very high response (an action potential)
  • This is due to the voltage threshold of the voltage-gated ion channels. Above the voltage threshold, they allow Na+ to flood into the cell, which causes depolarisation

Types of membrane potentials

Resting membrane potential

  • All excitable cells, usually -60 to -80 mV
  • This is the potential before stimulation. It is maintained by ion channels)

Action potential

  • Rapid response (to some stimulus) of about 100 mV.
  • Vm temporarily positive
  • Nerve impulse
  • Initiate muscle contraction

Synaptic potentials

  • Nerve response to neurotransmitter
  • Can cause depolarisation or hyperpolarisation

Receptor potentials

  • Response to sensory stimuli in specialised sensory receptors (e.g. photoreceptors, skin nerves, cochlea has finger-like stretch receptors that detect sounds)

Graded potentials

  • The depolarisation response is proportional to the size of the stimulus depolarisation (so there is no threshold voltage, just a direct relationship)
  • This is useful for graded muscle contraction
  • Don’t have an “all or nothing” response

All of these cells function by selective movement of ions and other solutes across their membranes

Salts in solution dissolve into ions

NaCl salt
  • As a solid, a salt is a strong ionic lattice of positive and negative charges
  • In water, ions are surrounded and stabilised by polar water molecules. This is called “hydration”
  • Ions (and other “polar” molecules) are hydrophilic and lipophobic (hate oils/lipid).

Circuit analogy

Consider the simple circuit:

  • The battery provides the driving force (12 V p.d. between the 2 terminals)
  • The circuit is complete when the switch is closed
  • The current is carried by electrons flowing in a conductor (wire)
  • The current flows through a resistor (light bulbs) to cause some response

In excitable cells:

  • The electrochemical potential provides the driving force
  • The switch is an ion channel
  • The current is carried by ions (cations in the figure below)
  • The response is depolarisation (which has other effects [that we will learn later] that are analogous to “resistance”)

Electricity considerations

  • Charge (Q or q) is a fundamental property of matter. Either positive or negative
    • Like = repel. Opposite = attract.
    • Measured in coulomb (C)
    • The elementary charge is the charge on a single electron (or monovalent ion) is 1.6*10^(-19) C
    • An electric field emanates from any charged point or surface
  • To separate charges requires work. Once separated, they possess potential energy
  • Potential difference (or voltage) (V) is the electrical difference in potential energy between charges in two different locations (1V = 1 J/C). [Or: one joule is required to move a charge of one coloumb against a potential difference of one volt]
  • Current (I) is the rate of movement of charge past a point per unit of time.
    • Measured in amperes, A.
    • 1 A = 1 C/s
  • Resistance (R) is a measure of how easily charge can move under a given voltage. R=V/I (Ohm’s Law). Conductance (g) = 1/R
  • Capacitance (C) is the ability to store separated charge.
    • Consider two conductors separated by an insulator
    • C is the charge separated divided by the potential difference thus produced (C=Q/V)
    • Accompanies the electrical potential across cells
    • The unit is farads (1F = C/V).
    • Stores charge whenever voltage changes

Determinants of ion movement

What determines whether an ion moves in or out of a cell?

  1. The ion must be first allowed to get across (permeate) the membrane via a channel (that lets ions in or out of the cell)
  2. The presence/absence of a concentration gradient (a chemical force) [by Fick’s Law of Diffusion (1855) ions will move down their concentration gradient]
  3. The presence/absence of an electrical potential across a cell membrane (ions are charged and so they are influenced by this potential (an electrical force). (E.g. if there is a negative potential inside the cell, then it will attract positive charges or repel negative charges)

2. and 3. comprise the electrochemical driving force of the cell.

The excitable cell membrane

  • Cells use energy to operate pumps and carriers to establish ion concentration gradients
  • Gradients across a membrane work like a hydroelectric power plant (in reverse) [see above]
  • See the graph of different ion concentrations exist inside and outside a cell

Transport through the membrane can be done through carriers and ion channels.

Carriers

  • Pumps and Carriers use energy to move solutes across the membrane.
    • They are active transporters. They move ions against their gradients
  • Ion channels allow solutes to diffuse across the membrane in accordance with their gradients
    • They are facilitated diffusion transporters
    • There is a constant flow of some ions across the membrane (contributes to the resting membrane potential).

Ion channels

  • Ion channels are proteins that traverse the membranes of all excitable cells.
  • When they open, they provide a hollow water-filled pore through which ions can pass.
  • By controlling opening and closing (“gating”) of these selective ion pores, cells across all species are able to produce and transduce electrical signals.
  • There are many types with different:
    • Ion selectivity
    • Stimuli to open (gating mechanisms)
    • Rates of opening and closing (gating kinetics)

E.g. Gramicidin A channel is secreted by some bacteria to kill other bacteria (below)

Electrical signals

Electrical signals are produced due to different ion concentrations inside and outside the cell combined with selective membrane permeability.

Propagation of action potentials

  • Cells communicate a signal from one part of the cell to another part
  • For example, the action potential propagates along a nerve axon

Intercellular communication

Cells communicate with each other by both chemical and electrical means

  1. Chemical communication
    • The motor nerve signals a muscle cell to contract by releasing a neurotransmitter chemical (Ach)
  2. Electrical communication
    • The smooth muscle cells of the gut contract together during peristalsis
    • Gap junction channels allow synchronised activity in adjacent cells

Underlying causes of positive and negative electrical potentials

  • The typical resting membrane potential is negative
    • K+ leaves the cell through a K+ channel to make the inside negative
  • If Na+ is allowed to move across the membrane, then the membrane potential becomes more positive (depolarisation)
  • If Cl- is allowed to move across the membrane, then the membrane potential becomes more negative (hyperpolarisation)

Protein structure is revealed by X-ray crystallography

In the right-hand picture, the top area (with the red “clasp”) is a selectivity filter. These determine which stimuli the gates respond to. Note that ion channels are large transmembrane proteins.