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Transmembrane Receptive Dimers as Molecular Tiggers Having Chemical and
Electrical Inputs

Arcady N. Radchenko
S-Petersburg Institute for Informatics and Automata RAS
radch@gw2.spiiras.nw.ru

The morphology and functional features of iono-, chemo - and
metabotropic receptors are analyzed. The conformation processes produced by
interaction of these receptors both with synaptic mediators and electric
field are searched. It is shown, that receptive cluster behaves as the
transmembrane molecular trigger. It's outer part interacting with mediator
composition transfers signal to and endocellular part controlling a
position of the catalytic center relatively to BLM so that a synthesis of
the "second messenger" occurs. We show how conformations of the receptive
cluster caused by electrical and chemical stimuli's as well as their
overlapping can control writing/reading mechanisms for memory learning,
engram consolidation and retrieving.

The olfaction detects some molecules; vision is sensitive to some
quantum of light. The so high sensitivity is ensured due "chemical gaining"
of sensory neurons: the conformation by one of receptive molecule activates
many molecules of transducin, each of them inactivates hundreds molecules
of cGMF and so on (Pribram, 1975). The bound energy delivers in such
metabolic chain. The primary signal will gain in 103 - 107 times in the
total, and the process is terminated by general depolarization of neuron
membrane with a spike generation.
The gaining processes are proper not only sensitive, but also central
neurons, where the local conformation transition LCT of the receptive
molecule, in potentiation condition, is capable to trigger a process of
membrane endogen depolarization (ED). If conformation triggering is not
accompanied by noticeable electrical responses, such spike is named
"spontaneous", "endogenous" or pacemaker". The primary triggering
mechanisms of a neural pulse in sensory and central neurons are similar:
these are local conformational transitions of receptive molecules. But
receptors of the sensory cell are attuned on particular outer stimulants;
meanwhile the neuronal receptors are detectors of neuromediator molecules
or their combinations. The highest sensitivity of the gating mechanism of
ED allows overcoming a rough mechanism of direct depolarization. The
roughness is predetermined, as is it known, by low capacitive impedance of
plasmatic membrane.
There are iono- and metabotropic receptors. The first are disposed
mainly on a subsynaptic membrane. Driving ion channels, they converse local
chemical signals in electrical one (PSP). In this form subsynaptic action
is spread much more widely - in the limits of cable membrane properties.
The activation of metabotropic receptors does not accompanied by
significant electrical signals, but resulting synthesis of second messenger
derives metabolic processes in the cell. An example of such activation is
potentiation of a neuron, including short- and long-time types. It ensures,
in particular, the mentioned gating properties of neuron cells. Both
receptor types ensure generalized membrane responses - PSP and
potentiation.
The receptors of the third type differ by that their responses are
local, though in potentiation condition they are capable to be developed in
process of endogen excitation of a neuron. The clusters of such receptors
may form trigger zones (TZ) on perisynaptic membrane. They sensitive both
to electrical and to chemical stimulus, their combined effect differs from
separate activity (Sokolov, 1981). These receptors can be in three
conformation states. Such receptors can trigger or not trigger the
generalized neuron response (spike) in dependence on the conformation
states. These states are saved irrespective of presence or absent of an
agonist (mediator), which initiated these transitions (Kenakin et al,
1995).
The receptor functions depend on properties of its three parts -
extracellular, transmembrane and endocellular (catalytic). The outer
receptor part reacts to mediator concentration, transmembrane part drives
ion channels and transmits a signal from a outer part into the cell, where
inside part catalyzes a synthesis of the second messenger. Extracellular
and the endocellular chains of the receptor are retained in relative
nearness and can interact through membrane, deriving numerous transmembrane
dimer links. Such dimers link is named as functional, because of their
connections are open (uncoupling dimers). They are supported by
electrostatic attraction of ionized amino acidic residues. In other words,
these interactions are ionic, but not covalent one. It is shown, that ion
interaction may be regarding as an attraction of gating charges - GC
(Radchenko, 1993). The receptors unite in clusters, where GCs form two
intramembrane heteropolar charge lattices.
Fig. 1 shows, how the electrical and chemical stimuli's control dimer
conformations by increasing or decreasing a distance between GCs and
causing depolarizing or hyperpolarizing conformation transitions (DCT or
HCT) respectively. The insertion of calcium ion in dimer linkage diminishes
the distance. These variations go to both sign of polarization in gape of
dimer lattices and their interaction detail.
[pic]
Fig.1. Influence of electrical and chemical stimulants to transmembrane
conformation transitions of receptive cluster inside BLM.

The analytical research allows knowing the features of these conformation
transitions. A Coulomb attraction of charged lattices Pe and elastic
counteraction force Pm (Hook's law) are presented by the formulas:
Pe = [pic], and Pm = Y [pic] , (1 and 2)

Where E is a field gradient between lateral ionization terminals of protein
molecule residues and ( is dielectric permeability; (0 and ( are initial
and current distances between opposite charges in layers; k(0 is a limiting
distance for GCs approaches, i.e. kinematical restriction of conformation
mobility of the charges; Y is elastic modulus of Young for side chains of
protein molecules. BLM is considered indefinitely hard, that corresponds to
constant ( 0. In of force equilibrium Pe + Pm + Ph = 0 we temporarily
eliminate hydrophobic and other forces Ph, which push or pull out the
charges from lipid layers. Substituting in balance of forces of their value
(1, 2), and adapting to relative variables y = (/(0, we get the following
formula for electrical control of conformation states and transitions of
receptive cluster (Radchenko, 1993): (3)
[pic] (3)
It features the volt-conformation characteristics (VCC) that shows how
relative distance y between the GCs depends on both membrane potential U
and restrictions on conformation motility of dimer k (Fig. 2). In
hysteretic modes (k < 0.308) the receptive cluster can be work as bistable
trigger or univibrator depending on membrane potential. In this case the
receptive cluster is the molecular trigger, which is characterized by two
stable convertible states (4-1 and 2-3) and two conformation transitions
named hyperpolarizing and depolarizing (HCT and DCT). If restriction of
conformation mobility is by k = 0.308 value, the given cluster behaves as
the Schmitt's trigger. In this case its VCC separates hysteretic and
monotonic conformation modes.
[pic]
Fig. 2. Conformation modes of the molecular trigger (transmembrane of
receptive dimer) in dependence on conformation restrictions k and membrane
potential U.

One of features of the molecular trigger is that its extracellular part
reacts with synaptic mediators, and intracellular catalyzes synthesis of
the second messenger.
The second feature is that the molecular trigger bounds the different
energies in two conformation states. Therefore one of transitions (HCT) is
accompanied by energy accumulation, and another (DCT) - by delivering. The
energy quantity is defined by the area of a hysteretic loop. It depends on
k, i.e. restriction on conformation mobility of GCs: the restrictions less,
the more hysteretic loop widely and more energy is delivered in DCT.
The third feature is, that the changes of conformation states 1-4 and 2-
3 are accompanied a) by immerging and emersion of receptor terminals on the
both BLM sides and accordingly b) by increasing (HCT) and decreasing (DCT)
of intramembrane pressure, which closes and opens ion channels. DCT is
accompanied by an expulsion of the catalytic receptor center from BLM
inside the cell and opening of ion channels with following postsynaptic
potential (PSP) appearing. The synthesis of the second messenger supported
by delivered energy (phonon, conformon) and generating PSP, which, in
effect, also is the second messenger, but electrical one.
The fourth feature is related to GC immobilization (restrictions of
conformation motility, when k( 1) and inactivation of ion channels after
DCT. The immobilization is caused due to parts of receptors in the upper
conformation state 3-4 being emerged from BLM may be adhered (Schmidt,
1995) and then polymerized (Avissar et al, 1983). These processes caused by
receptor clusterization appear as formation "patches" and then "caps". In
effect VCC evolutes (finger k) losing hysteretic properties. This process
is known due to inactivation of ion channels conductivity (Radchenko,
1996). The schematic of this process is shown in a Fig. 3, where the stages
a, b, c, d and e correspond to state notations in Fig. 2.
The duration of these processes b ( c (d correlates with a time for
consolidation of memory trace. The states "c" and "d" are related to data
retention in short- and long-term memory respectively. This dividing is
conditionally and signed by (c + d), as adhesion and polymerization
processes are bridged in time. To return a receptive cluster in an initial
conformation state (recovery from inactivation - (k) is possible by means
membrane hyperpolarizing. It is accepted by term conditioning (Armstrong,
Bezanilla, 1979). The resulting conformation transition (amnesia) we
designate by the "e" character.
[pic]
Fig. 3. The formal schematic of conformational changes of receptive
cluster: a - approached dimers "; b - " the disconnected dimers"; receptive
cluster formation: c - activity of interreceptor adhesion; d -
polymerization of receptors (forming "caps"), e - recovery from
inactivation. The schematic of Ca2 + embedding in dimers is unknown.



Fig. 3 and 4 show that, there is bifurcation of conformation process in
state "b": the cluster can return a state "a" or pass in "c". Apparently,
the recovery "b ( a" (HCT) will occur in R conformation mode (see fig. 2)
because of the greater membrane polarization (the square-law force
dependence on potential). Consequently, only W mode ensures sufficient time
for retention in a state "b" and transit "b ( c".





Fig. 4. The schematic of conformational changes of receptive cluster.





The situation with a bifurcation (b ( a or b ( c) clears up after
viewing features of chemotropic conformation transition. A direct action of
mediators on the receptive cluster illustrates Fig. 5, where balance of
forces, Pe + Pm + Pc = 0, is added by force (Pc), acting among mediator and
extracellular part of receptive cluster. The formula
Pc = C 2 ( 2 / (,
(4)

is valid for Pc estimation, though the formula has being drawn by Coster
(1975) for variable proton concentration Ci . In result we get
generalization of a set VCC, shown in a Fig. 5 in relative coordinates
y = (/(0. Fig.5 differs from VCC in a fig. 2 by that is tied three
parameters - concentration of an exciting mediator C (С0 potential U and variable restriction on conformation mobility of GCs (in
this case this quantity is fixed, k = 0.23 to not black out a
delineation,).
A


Fig. 5. The schematic of chemotropic mediator action onto receptive cluster
and related VCC. Above: the vertical arrows display a direction of forces
and their value. A horizontal arrow shows intramembrane pressure. The
opening of an ion channel (IC) produces depolarization that gains effect of
chemotropic activity (positive feed back). If the canal and related EPSP
are missed, then arisen spike is recognized as "spontaneous". Bottom: VCC
display increasing of the area of hysteretic loop (energy CCT)






B
[pic]

As follows from a drawing, the hysteretic loops for these VCCs are
extended. It ensures increase energy pulse that accompanies DCT "a ( b".
This transition occurs due increasing of mediator concentration at constant
membrane potential (vertical finger). Thus it is better to name it not
depolarizing, but chemotropic transition (CCT). The schematic of balance of
chemical, electrical and mechanical forces on a membrane is represented in
Fig 5a. It is clear, that the increase of intramembrane pressure caused by
hyperpolarizing closes the ion channel (IC), and the decrease caused by
depolarization or mediator action leads to IC opening.
If CCT is supported additionally by EPSP, the depolarization prolongs a
conformation state "b" due to relaxing electrostatic field inside dimer.
Its halves emerge and surface adhesive forces have a time to send
conformation process in the direction " b ( (c + d)"", that corresponds to
VCC hysteresis loss and consolidation of the cluster as soon as forming a
memory trace unit.
[pic]
Fig. 6. The schematic of ionotropic "v", chemotropic "x" and
metabotropic activities of mediators. First two of them produce
depolarizing or chemotropic conformation transitions respectively (DCT or
CCT) of a ( b type, and triggering of the mechanism of endogen
depolarization (ED) of cell (is marked by a rectangle). The accord of
signals m+x retains a conformation "b" on a time that is sufficient for
initiating of adhesive and polymerizing processes as well as for
transformation of "b" conformation in "patch" and then in "cap". We
suppose that potentiation of gain processes depends on activity of
metabotropic receptors.

Therefore, the feature of a combined effect of chemical and electrical
stimuli's from their separately actions can be presented by the Fig. 6.
Here conformation transitions in limits of a hysteretic loop (a ( b) caused
by chemical or electrical stimuli's correspond to the lower oval. Their
united activity directs a cluster in GC immobilize state (above dotted
oval), which is fixed by an adhesion and polymerization and forming the
patches and caps. A specialization of different receptor types there is
shown too.
[pic]
Fig. 7. The schematic of triggering of endogen spike.

MS - metabolic start endogen spike, ED - endogenic depolarization; DD -
direct depolarization of trigger zone of neuron; DCT and HCT - de- and
hyperpolarizing conformational transitions of receptive cluster on SD-
membrane; BS, US and IS are bottom , upper and inactivated states on
hysteretic (k = 0.15) and monotonic (0.65) VCC of receptive cluster; t z
is critical time for engram transition in a long-term memory. The
metabolic gaining of trigger pulses caused CCT or DCT depend on neuron
potentiation. The arrow A displays a result of inactivate transition from
VCC-1 (k = 0.15) to VCC-3 (k = 0.65). The wave fingers show accumulation
of energy by cluster at HCT and its releasing at DCT.

The more complete relations between functions of a nervous cell are
shown on Fig. 7. The central moment here is the metabolic start (MS) of
processes of endogen depolarization (ED) of a membrane following in direct
depolarization (DD) of a neuron. The trigger pulses ensure with chemical or
electrical stimulants, which produce accordingly CCT and DCT. The first
realizes the much greater energy pulse and therefore should be considered
as basic. However electrical signals are important for memory learning. It
is shown on VCC at the left, where CCT-DCT translate a cluster in the upper
conformation state (US), which is returned in the low state (LS) by means
of HCT or is not returned (at CCT+EPSP), transferring in an inactivated
state (IS). Requirement for bifurcation is delay in US: the initial
conformation is restored if t < tz, but cluster can transit in patch and
then cap if t > tz .
The surveyed receptor types are shown on Fig. 7, including the most
investigated ionotropic receptors that form EPSP and IPSP. The first
produce DCT and partly influence on direct depolarization of neuron (dotted
line). If this depolarization is small or misses, the spike usually name as
"spontaneous". Metabotropic receptors ensure "pumping" of the metabolic
amplifier. Mediator sources for this function can be not located only
proximate synaptic vicinity, but also removed and not having direct
contacts to the cell (Contant et al, 1996). This is so-called volume
transmission of mediators (Agnati et al, 1995, Zoli et al, 1996). Figure
shows that the same function fulfills IPSP (off-response). In bottom of the
drawing we show a location of receptors on soma-dendrite membrane. The
locating of receptive clusters relates synaptic environment is very
important. The address properties of synapses and presynaptic vicinity were
published earlier (Radchenko, 1993; 1998; 1999, 2002).

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