The
auditory information coded by quantized energy of a sound wave are transmitted
from the auricle, the middle ear and the bone capsule of the oval window onto
the bony labyrinth of the cochlea, to crista spinalis and to the hearing
receptor. The transmission occurs by means of a sound wave that transmits the
encoded information to the receptor that receives the signals and forwards them
to the auditory cell. Further analysis and processing of the information takes
place in the auditory cell [7]. Low frequencies are easily transmitted via all
the media, and are also transmitted via the cochlear fluid with the reservation
that the information is forwarded by a sound wave without the mass of the
environment being moved. The mechanism for receiving and processing the
information operates on a sub molecular and electron level. A stimulus adequate
for the hearing organ is the energy of a sound wave transmitted via the
vibrating particles of the medium to the receptor. All the atoms in the matter
of the medium that the sound wave propagates in and the molecules and atoms
that form the hearing receptor are in constant motion. It is a progressive
motion – oscillatory and rotary motion or a combination of the above. Motion is
related to kinetic energy of molecules, which also have potential energy that
is the energy of chemical bonds, electrostatic attraction forces, and
electromagnetic interactions. The sum of these energies forms the inner energy
of a molecule. The total inner energy is also determined by temperature and the
mass of a molecule. Providing external energy sound wave energy specifically
when it comes to hearing to the molecule of the hearing receptor causes a rise
in the internal energy of a sound-sensitive molecule that receives the signal
[8]. The vibrating particles of a sound wave in a medium have either a positive
charge, a negative charge or a neutral charge. Neutral ones transfer potential
energy determined by the speed of vibrations and frequency, as well as electron
energy by means of contact between electron clouds of molecules. Electrons form
an electron cloud around a nucleus of an atom. The size of that cloud depends
on the number of orbits that electrons are situated on. An electron can change
an orbit; however, in order to go to an orbit that is closer to the nucleus, an
electron needs to receive additional energy. Going from orbit 2 to orbit 1
requires 3.4 eV. These jumps are quantized, meaning that there is either a jump
or no jump without any transitional option. If an atom in a molecule of the
acceptor receives a quantum of energy from another atom or a particle (from a
sound wave), then the electron of the acceptor jumps to an orbit that is closer
to the nucleus its inner energy increases incrementally in a quantized manner.
This puts the atom in the so-called excited state which, unlike the ground
state, is impermanent as it lasts ca. 10-8 of a second, followed by an
immediate attempt to return to the ground state by means of emitting 1 photon
of energy – in situations where the issue pertains to 1 atom jumping 1 orbit.
If in a combination of a receptor molecule + energy of the sound wave there is
an unlimited number of such jumps, then there is 1020 combinations of various
kinds of quantized energy being transmitted. This gives an unlimited number and
variety of transmitted information. The time required for simple changes in
energy between the molecules is 10-14 s. More complex conversions take 1000
times longer; nonetheless, that is still 10-11s. The energy that codes the
information of sound-sensitive molecules that receive this information from a
sound wave is forwarded to molecules responsible for gating
mechanically-activated potassium ion channels. The transferred energy acts on
the activation and inactivation gates of the potassium channel that determine
the influx of potassium from the endolymph to the auditory cell. Sound wave
energy causes changes in the rotation of atoms, alters angles in the bonds,
oscillation, leading to changes in the conformation of molecules; by means of changing
their size and dimensions, the conformers that are formed fulfil a role
consisting in closing and opening of an ion channel. The mechanically-activated
potassium channel has a selectivity filter that ensures inflow of potassium
ions only. With the potassium channel fully open, in 1 ms, as many as 6,000
potassium ions flow from the endolymph into the auditory cell. The influx of K+
ions inside the cell triggers its depolarisation. With the threshold of 10 mV
exceeded, potential-dependent Ca++ ion channels are activated. Local
depolarisation increases, more and more Ca++ channels dependent on
depolarisation and voltage-dependent Na+ channels on the lateral surface of
auditory cells open up. The interior of the cell has a negative charge of - 80
mV owing to a high number of proteins whose charge is negative and continuously
active sodium potassium pumps. Outside the cell, the level of Na+, Ca++ and Cl-
is high which combined with a high electric potential forms a high
electrochemical potential for sodium and calcium ions. The influx of Ca++ ions
into the cell causes a release of calcium ions from mitochondria, the
endoplasmic reticulum and the nucleus of the cell. The calcium level outside
the cell is 10,000 higher than the baseline calcium level inside the cell,
which can become even 100 times higher inside the cell. Following excitation,
membrane potential changes to receptor potential. Inside the cell, calcium is
combined with calcium-depended proteins, thus altering their properties. The
information is split between constitutive activities related to regular work of
a cell and to regulated ones which are related to production, transport, and
release of the transmitter. Once the calcium level has been increased and the
information has been transferred, the calcium level inside the cell is rapidly
reduced. Calcium pumps are and ion exchangers that expel calcium ions outside
the cell are working, and some of the calcium is transported to mitochondria,
the endoplasmic reticulum, and the nucleus. Intracellular messengers, varying
calcium levels, and the activity of intracellular proteins are responsible for
intracellular amplification. The cellular membrane at rest is most permeable
for potassium ions and for that reason, the value of the resting potential of the
cell membrane is close to the resting potential of potassium. The natural drive
to balance out the concentration and the voltage on both sides of the membrane,
which is consistent with the second law of thermodynamics, consequently
eliminates the membrane potential. This is counteracted by the presence of ion
pumps and ion messengers, the active mechanism that creates a difference in
voltage and potential on both sides of the membrane. This produces a chemical
and electric gradient. In the case of auditory cells, there is a unique
situation since the side and bottom walls of these cells are in contact with
the perilymph or the interstitial fluid characterised by a low potassium ion
level and a high sodium ion level (K+ 7-8 mEq/l, Na+ -140 mEq/l), whereas auditory
hair cells and the top part of the auditory cell are surrounded by the
endolymph with a very high potassium concentration and a low sodium
concentration (K+ -150 mEq/l, Na+ -15 mEq/l). The activity of ion channels is
affected by phosphorylation and dephosphorylation of channel proteins, ATP
concentration inside and outside the cell, cAMP and cGMP levels, and the cell’s
pH, mechanical energy (the sound wave), osmotic pressure, the
oxidation-reduction potential, or the presence of ligands. A mechanism of great
importance for hearing is proteins – sound-sensitive molecules sensitive to a
given frequency and intensity of a sound wave, genetically conditioned, which
react to an adequate stimulus the sound wave energy that codes all the
information. The energy of a sound wave causes an influx of potassium ions into
the cell but at the same time, these ions are flowing outside the cell via
potassium leak channels in the side wall of the cell. A specific balance in the
K+ levels is preserved. An overly low inflow of K+ ions through the
mechanically-activated potassium channels of the hair cells does not affect
this balance. Once a certain limit called the threshold is exceeded, a cascade
of consequences occurs inside the cell alone. The higher the density of potassium
ion channels on the hair cells and in the top part of the auditory cell, the
lower the excitation threshold for that auditory cell is. It is doubtful
whether only one potassium channel is used for every two hair cells [9].
Potassium ions with a positive charge that flow into the cell from the
endolymph cause depolarisation, which is a factor that triggers conformation
changes in proteins that are responsible for the transport capacity of
voltage-dependent calcium and sodium ion channels in the side wall and the
bottom part of the cell. Sodium channels react to an excitation in a much
quicker way than potassium channels; hence, the cell membrane becomes permeable
for sodium ions first. The elctro-chemical potential is much higher for sodium
ions than potassium ions. The force that drives ions is greater and affects the
speed of the sodium ion influx into the cell. The growing depolarisation is
conducive to opening of more and more sodium channels. A positive feedback loop
occurs: the inflow of sodium ions increases depolarisation and depolarisation
causes new ion channels to open up, resulting in a swift depolarisation of the
auditory cell. The membrane potential nears the balance potential for sodium
ions, whereas the electric potential – which is the force that drives these
ions – ears zero. The force that drives potassium ions grows. The opening of
more and more voltage-dependent potassium channels obstructs depolarisation.
The factor that rapidly obstructs depolarisation is the phenomenon of inactivation
of Na+ ion channels. After about 1-2 ms from the opening of the channel, they
are inactivated – at that time, they are being closed and rendered unsensitive
to stimulation. The inflow of potassium via the potassium channels in the side
wall of the call and the inactivation of sodium channels lead to a reverse
situation, where the cell is repolarised and hyperpolarisation occurs, which is
a stimulus for closing the potassium channels and a return to a balanced state.
Repolarisation and hyperpolarisation cause sodium channels to go from the
inactive state to the closed state, sensitive to re-stimulation. The membrane
potential goes back to the balanced state. A full work cycle of a sodium ion
channel (activation, opening, closing, inactivation) is ca. 4-5 ms, which
offers the possibility to receive the information carried by the sound wave to
the frequency of 250 Hz, assuming that at the same time the entire auditory
cell becomes depolarised. Receiving higher frequency sounds requires a higher
number of ion channels activated at various points in time that transfer the
information to the synapse without the auditory cell undergoing depolarisation
and contraction all at once. The calcium channels in the side wall of the
auditory cell is where the influx of Ca++ ions makes its way into the cell. The
calcium level inside the auditory cell is ca. 100 nM/l, whereas in the
interstitial fluid, it is ca. 1,200,000 nM/l. The vast amount of the calcium in
the cell is stored in the endoplasmic reticulum and the organelles of the cell.
The depolarisation of the cell and the inflow of calcium is a signal for it to
be released from the intracellular reserves. The calcium inflowing through the
ion channels along with the calcium released from the cellular storage sites spreads
inside the auditory cell. As a result of the growing concentration of
cytoplasmic calcium ions, they are bound with specific proteins that are
activated in this manner, thus increasing the activity of various prote in
kinases. For this mechanism to be able to work, there needs to be a mechanism
responsible for reducing the calcium level inside the cell in a very swift
manner decrease after the information is transferred. This is the task of the
pump that discharges the Ca2+ ion outside the cell in return for 2 H+ ions that
are imported into the cell. The Ca2+H+ATPase is working, which derives energy
from ATP. Another mechanism that lowers calcium levels in the cell is
counter-transport dependent on the concentration of Na+ ions, which exchanges
two Na+ ions from the extra-cellular space for one Ca2+ ion that is discharges
outside the cell. The third mechanism is ion pumps that move calcium ions from
the cellular fluids to the organelles, mainly mitochondria, the endoplasmic
reticulum, and the nucleus.
Calcium
regulates numerous intracellular mechanisms, its key task being taking part in
the transfer of the intracellular information, as well as amplifying and
disseminating it. This consists in Ca2+ ions affecting the following enzymes:
adenylyl cyclase, phosphodiesterase, phospholipase A2, protein kinase A.
Calcium ions are the second messenger and participate in the forming of other
second messengers such as cAMP, cGMP, IP3, and DAG. Intracellular amplification
works by means of second messengers and Ca2+ receptors. Once bound with
calcium, these proteins change their biological properties and affect other
proteins thus impacting cellular reactions. There are many Ca2+ receptors; a
particularly significant one is calmodulin, which has four calcium-binding sites.
With subsequent ions connecting to the binding domains, conformational changes
in the calmodulin particle occur, thus increasing its ability to bind with
enzyme particles. Enzyme activation takes place once at least three Ca2+ ions
are connected. At the calcium level of 10-6 mol/l inside the cell, the activity
of the calmodulin-calcium complex is 1000 times greater than the activity of
the calmodulin alone.
It
is one of the key elements of intracellular amplification [10]. This complex
acts directly on enzymes or indirectly by stimulating calmodulin-dependent
protein kinases that by means of enzymatic protein phosphorylation transform
them into an active form. The stage of transferring the information in the
auditory cell related to calmodulin leads to the signal being split in
different directions. The amplified signal continues to be forwarded towards
the centre but at the same time, calmodulin is activating many so-called
constitutive processes, that is, processes that occur in a non-excitable cell. The
second system activated by the calmodulin-calcium complex consists in
regulating the co-activity of all the organelles of the cell. The third one,
relatively slow, consists in regulating the production of proteins,
particularly enzymatic proteins. Changes can affect the process of generating
enzymes or the speed at which they are broken down. The speed of the reaction
is also affected by enzyme activators and inhibitors. These three process
regulation systems cooperate to ensure that constitutive and regulated
processes are well coordinated. Calcium is an information transmitter that
precedes the formation of other second messengers (cAMP, cGMP, DAG, IP3) that
are produced by enzymes stimulated by a spikein the calcium levels or activated
by proteins G. The stage of producing second messengers is one of several
mechanisms of intracellular amplification. A single particle of the enzyme can
produce hundreds of second messengers. The energy of an external signal that
triggers a chain of intracellular reactions causes constitutive and regulated
processes in the cell to be launched. Their intensity is proportionate to the
energy of the external signal. Pathways for transmitting intracellular
information are started. Second messengers are watersoluble and can rapidly
move inside the cell. The processing of the information in the cell and
transferring the information forward is related to the reversible formation and
hydrolysis of phosphodiester bonds. The forming of bonds is the task of
kinases, whereas hydrolysis is the responsibility of phosphatases. Each cell
has a set of ca. 1000 various kinases. Kinases are tasked with protein
phosphorylation that alters conformation of these proteins, thus rendering them
active and capable of stimulating other proteins, generating a wave of protein
activation on a signalling pathway. Phosphorylation is an “activate and
forward”-type of activity, whereas when it comes to phosphatases, which are
just as abundant in the cell as kinases are, they operate on a “deactivate-end
of information” principle. Information transfer is an endergonic process that
requires an input of energy from a high-energy compound such as ATP or GTP
being broken down. Two types of hydrolase enzymes are operating, namely,
ATPases and GTPases, proteins acting as intracellular molecular switcher. An
auditory cell functions in line with two programmes; the first one involves the
cell living as the baseline unit of the body; the other one concerns processing
auditory information. Both these programmes cooperate, often using the same
information transfer pathways, the same substrates, and the same enzymes.
The
mechanical energy of the external signal, conversed into the electric energy of
the membrane potential, and then transformed into the chemical energy of ionic
and covalent bonds, and intracellular messengers, becomes amplified and split
into two systems. The lower the energy of the external signal the greater the
amplification. A high-intensity sound is accompanied by the phenomena o
adaptation and inhibition. The end product of these transformations (a
transmitter) serves as a tool in the information transfer system. The forming
and storing of the product are regulated by the first system (the constitutive
system), whereas the discharge of the transmitter to the synapse is part of the
other system – the regulated system. If an external signal that is above the
threshold intensity generates a 10-9 V potential on the membrane of the
receptor cell, then that energy must be amplified many times to make it capable
of reaching the central nervous system. The signal inside the cell which is a
portion of energy moves in the form of a wave at the speed of ca. 0.5
millimetre per second. The frequency of calcium waves codes the information
related to the frequency of the sound wave, while the transferred energy is
consistent with the intensity of the sound. A rise in the calcium level in the
presynaptic area serves as a signal for releasing a portion of the transmitter
into the synapse. The amount of the transmitter is proportionate to the
intensity of the sound. Synaptic vesicles are moved by means of anterograde
transport in the moment when calcium-activated proteins break down the protein
bonds that fix the vesicles to the cytoskeleton. The molecular driving force that
moves the vesicles towards the presynaptic membrane is kinesin. The protein
complex in the presynaptic area facilitates contact between the vesicles and
the presynaptic membrane, the bonding of the two and the forming of a channel
that links the interior of a vesicle with a synapse. Retrograde traffic is the
task of a protein called dynein. These membranes that are moving back are used
for creating new synaptic vesicles. This is called cell membrane recycling. The
discharge of a transmitter to a synapse involves a transfer of a bit of
information whose intensity and frequency match that of the signal. A synaptic
gap about 50 nm wide is filled with a fluid in which the transmitter moves from
the presynaptic membrane to the postsynaptic membrane, and then connects to
specific ion channels causing them to open. The transmitter is active only for
a period of ca. 1 millisecond, after which it disconnects from the ion channel
and is broken down by the enzymes present in the synaptic gap. The level of a
transmitter falls rapidly, after which ion channels become sensitive to a new
influx of that transmitter. On the postsynaptic membrane, a depolarising
potential is formed, the so-called excitatory postsynaptic potential (EPSP). If
a given depolarisation threshold is exceeded, which is ca. 15 mV, then this
depolarisation moved along the afferent nerve to the next synapse, towards the
ganglion cell. Synaptic transmitting is related to many regulatory mechanisms
such as pre- and post-synaptic inhibition and aggregation, spatial aggregation,
temporal aggregation, enzymatic degradation, and transmitter reabsorption. In
the synapse, a process of encoding the transferred information occurs. The
encoding consists in arranging the quantity and size of impulses in a nervous
fibre or a bundle of fibres depending on the intensity and the frequency of the
sound. In each subsequent synapse, the information is then decoded, the
electric signal is transformed into the chemical energy of the transmitter, the
basic information that reaches the synapse is integrated with the additional
information from interneurons, and the chemical energy is converted into
electrical energy of the postsynaptic stimulating potential with simultaneous
coding. Having crossed though several synapses and intrasynaptic sections, the
information in the form of energy pulses reaches the central nervous system. It
is the decoded, subjected to an analysis similar to Fourier analysis, and
compared with the information recorded in longterm memory. An image of hearing is
recorded in the memory, which can be re-accessed even many years later.