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General Overview of Signalling in the Nervous System

2.1 Intercellular signalling: Wiring and volume modes of transmission

The fundamental question in understanding brain function is: 'How do cells in the nervous system communicate?' At the very dawn of experimental neuroscience two fundamentally different concepts were developed. The 'reticular' theory of Camillo Golgi postulated that the internal continuity of the brain cellular network works as a single global entity, while the 'neuronal-synaptical' doctrine of Sigmund Exner, Santiago Ramón y Cajal and Charles Scott Sherrington implied that every neurone is a fully separate entity and cell-to-cell contacts are accomplished through a specialized structure (the synapse), which appears as the physical barrier (synaptic cleft) between communicating neurones (Figure 2.1). The latter theory postulated the focality of the intercellular signalling events, whereas Golgi thought about diffused transmission through the neural reticulum, which may affect larger areas of the CNS. The synaptic theory was victorious, yet the nature of the signal traversing the synaptic cleft was the subject of the second 'neuroscience' war, between followers of John Carew Eccles, who believed in purely electrical synapses, and supporters of Otto Loewi, Henry Dale and Bernhard Katz who championed chemical transmission. This clash of ideas lasted for about 20 years before Eccles yielded and fully accepted the chemical theory. For a while everything calmed down and the neuronal chemical synapse theory looked unassailable. The cornerstone of this theory implied focal information transfer through synapses, and the brain can be relatively simply modelled as a precisely wired system of logical elements. As usual, nature appeared more complicated than our theories, and now we have to admit that several different modes of cell-to-cell communication are operational within the CNS.

Schwann Cell

Figure 2.1 Chemical and electrical synapses. Signals between neural cells are transmitted through specialized contacts known as synapses (the word 'synapse' derives from term 'synaptein' introduced by C. Sherrington in 1897; this in turn was constructed from Greek 'syn-' meaning 'together' and 'haptein' meaning 'to bind').

Figure 2.1 Chemical and electrical synapses. Signals between neural cells are transmitted through specialized contacts known as synapses (the word 'synapse' derives from term 'synaptein' introduced by C. Sherrington in 1897; this in turn was constructed from Greek 'syn-' meaning 'together' and 'haptein' meaning 'to bind').

In the case of chemical synapses, cells are electrically and physically isolated. The chemical synapse consists of presynaptic terminal, synaptic cleft (~20 nm in width) and postsynaptic membrane. The presynaptic terminal contains vesicles filled with neurotransmitter, which, upon elevation of intracellular free Ca2+ concentration within the terminal, undergo exocytosis and expel the neurotransmitter into the cleft. Neurotransmitter diffuses through the cleft and interacts with ionotropic and/or metabotropic receptors located on the postsynaptic membrane, which in turn results in activation of the postsynaptic cell.

In the case of electric synapses, adjacent cells are physically and electrically connected through trans-cellular gap junction channels, each formed by two connexons (see Chapter 5.4). The trans-cellular channels permit passage of ions, hence providing for the propagation of electrical signalling, as well as larger molecules, providing for metabolic coupling

Firstly, the direct physical connections between cells in the brain are of a ubiquitous nature. Gap junctions (Figure 2.1), which are in essence big intercellular channels, connect not only glial cells but also neurones, and possibly even neurones and glial cells. These gap junctions function as both electrical synapses (which allow electrotonic propagation of electrical signals) and as tunnels allowing intercellular exchange of important molecules such as second messengers and metabolites. Secondly, neurotransmitters released at synaptic terminals as well as extra-synaptically, and neuro-hormones secreted by a multitude of neural cells, act not only locally but also distantly, by diffusing through the extracellular space.

These discoveries led to an emergence of a new theory of cell-to-cell signalling in the nervous system, which combines highly localized signalling mechanisms (through chemical and electrical synapses), generally termed as a 'wiring transmission' (WT), with more diffuse and global signalling, which occur through diffusion in the extracellular space, as well as in the intracellular space within syncytial cellular networks; this way of signalling received the name of 'Volume Transmission' (VT), which can appear as extracellular (EVT) or intracellular (IVT). There are fundamental functional differences between wiring and volume transmission: wiring transmission is rapid (100s of microseconds to several seconds), is extremely local, always exhibits a one-to-one ratio (i.e. signals occurs only between two cells), and its effects are usually phasic (Figure 2.2). In contrast, volume transmission is slow (seconds to many minutes/hours), is global, exhibits a one-to-many ratio (i.e. substance released by one cell may affect a host of receivers), and its effects are tonic. Extracellular volume transmission in the CNS is rather well characterized, e.g. in open synapses, in signalling mediated by gaseous neurotransmitters such as nitric oxide (NO), in actions of neuropeptides, which are releasedextra-synaptically,inpara-axonaltransmissionetc. (Figure 2.3). Theconcept of intracellular volume transmission is relatively new, and so far it is believed to be confined mostly to the astroglial syncytium. The substrate of intracellular volume transmission is represented by gap junctions. Gap junctions also form electrical synapses, which are a classical example of wiring transmission (very focal and extremely fast). Yet, the same channels are instrumental for long-distance

Wiring transmission Volume transmission

Astroglial Gap Junctions

Figure 2.2 General principles of 'Wiring' and 'Volume' transmission. Wiring transmission is represented by chemical synapses, the most typical of the CNS; synapses are tightly ensheathed by astroglial membranes, which prevents spillover of neurotransmitter from the synaptic cleft, and ensures focal signal transfer (arrows). Wiring transmission is also accomplished by electrical synapses, which allow rapid and local transfer of electrical signals. Volume transmission is generally produced by the diffusion of neurotransmitter from a focal point to several cells

Figure 2.2 General principles of 'Wiring' and 'Volume' transmission. Wiring transmission is represented by chemical synapses, the most typical of the CNS; synapses are tightly ensheathed by astroglial membranes, which prevents spillover of neurotransmitter from the synaptic cleft, and ensures focal signal transfer (arrows). Wiring transmission is also accomplished by electrical synapses, which allow rapid and local transfer of electrical signals. Volume transmission is generally produced by the diffusion of neurotransmitter from a focal point to several cells

Schwann Cell

Figure 2.3 Examples of volume transmission in the nervous system. Volume transmission in the nervous system can take various routes:

A. Neurotransmitter spillover: in synapses that are not perfectly covered by astroglial membranes, neurotransmitter may leak ('spillover') from the synapse and diffuse through the extracellular fluid to activate distant neuronal or glial cells.

B. Open synapses: neurotransmitters or neurohormones may be released from open synapses, which do not have defined postsynaptic specializations (e.g. catecholamine release from vari-cosities).

C. Ectopic neurotransmitter release: neurotransmitters may be released from sites other than at the synapse (ectopic release).

D. Neurosecretion: neurohormones can be released directly into the extracellular fluid and enter the circulation.

E. Release of 'gliotransmitter' from astrocytes: neurotransmitters can be released from astroglia via vesicular or nonvesicular routes to diffuse through the extracellular fluid and act on neighbouring cells.

F. Release of gaseous transmitters: e.g. nitric oxide, which act solely through volume transmission.

G. Intracellular volume transmission: second messengers or metabolites can spread through gap junctions providing for intracellular volume transmission.

(Adapted and modified from Sykova E (2004) Extrasynaptic volume transmission and diffusion parameters of the extracellular space. Neuroscience 129, 861-876; Zoli M, Jansson A, Sykova E, Agnati LF, Fuxe K (1999) Volume transmission in the CNS and its relevance for neuropsychopharmacology. Trends Pharmacol Sci 20, 142-150)

diffusion of molecules through glial networks, and as such they are involved in signal propagation on a one-to-many (cells) ratio. In fact, the same mechanism may be instrumental in neuronal networks, particularly in the developing CNS, as neuroblasts and immature neurones exhibit high levels of gap junctional coupling.

These three principal pathways of signal transmission in the brain, working in concert, underlie CNS information processing, by integration of all neural cells -neurones and glia - into highly effective information processing units. This is the concept of the functional neurone-glial unit.

2.2 Intracellular signalling

Intracellular signalling involves specific molecular cascades that sense, transmit and decode external stimuli. In the case of chemical neurotransmission, intracel-lular signalling invariably involves plasmalemmal receptors that sense the external stimulus, and effector systems, which can be located either within the plasmalemma

Schwann Cells

Figure 2.4 Ionotropic and metabotropic receptors. Ionotropic receptors are represented by ligand-gated ion channels. Neurotransmitter (NT) binding to the receptor site opens the channel pore, which results in ion fluxes; these in turn shift the membrane potential producing depolarization or hyperpolarization, depending on the ion and transmembrane electrochemical gradients. Metabotropic receptors belong to an extended family of seven-transmembrane-domain proteins coupled to numerous G-proteins. Activation of metabotropic receptors results in indirect opening of ion channels or in activation/inhibition of enzymes responsible for synthesis of different intracellular second messengers

Figure 2.4 Ionotropic and metabotropic receptors. Ionotropic receptors are represented by ligand-gated ion channels. Neurotransmitter (NT) binding to the receptor site opens the channel pore, which results in ion fluxes; these in turn shift the membrane potential producing depolarization or hyperpolarization, depending on the ion and transmembrane electrochemical gradients. Metabotropic receptors belong to an extended family of seven-transmembrane-domain proteins coupled to numerous G-proteins. Activation of metabotropic receptors results in indirect opening of ion channels or in activation/inhibition of enzymes responsible for synthesis of different intracellular second messengers

List Ligand Gated Ion Receptor

Figure 2.5 Specific examples of ionotropic and metabotropic receptors: Ionotropic Receptors. The most abundant ionotropic receptors in the nervous system are represented by ligand-gated cation channels and anion channels. Ligand-gated cation channels are permeable to Na+, K+ and to various extents, Ca2+, e.g. ionotropic glutamate receptors, ionotropic P2X purinoreceptors and nicotinic cholinoreceptors (nChRs); activation of these receptors depolarize and hence excite cells. Ligand-gated anion channels are permeable to Cl-, e.g. GABAa and glycine receptors; activation of these receptors in neurones causes Cl- influx, hence hyperpolarizing and inhibiting the cells, but in glia (and immature neurones) their activation results in Cl- efflux, because intracellular Cl- concentration is high, and hence they depolarize the cell.

Figure 2.5 Specific examples of ionotropic and metabotropic receptors: Ionotropic Receptors. The most abundant ionotropic receptors in the nervous system are represented by ligand-gated cation channels and anion channels. Ligand-gated cation channels are permeable to Na+, K+ and to various extents, Ca2+, e.g. ionotropic glutamate receptors, ionotropic P2X purinoreceptors and nicotinic cholinoreceptors (nChRs); activation of these receptors depolarize and hence excite cells. Ligand-gated anion channels are permeable to Cl-, e.g. GABAa and glycine receptors; activation of these receptors in neurones causes Cl- influx, hence hyperpolarizing and inhibiting the cells, but in glia (and immature neurones) their activation results in Cl- efflux, because intracellular Cl- concentration is high, and hence they depolarize the cell.

Metabotropic Receptors. In the CNS, these are coupled to phospholipase C (PLC), adenylate cyclase (AC), and ion channels. Metabotropic receptors coupled to PLC produce the second messengers InsP3 (inositol-1,4,5-trisphosphate) and DAG (diacylglycerol) from PIP2 (phopshoinositide-diphosphate), e.g. group I metabotropic glutamate receptors and most P2Y metabotropic purinoreceptors. Metabotropic receptors coupled to AC produce cAMP (cyclic adenosine-monophosphate), e.g. group II and III metabotropic glutamate receptors, P2Y purinoreceptors, and some muscarinic cholinoreceptors (mChRs). Metabotropic receptors coupled to potassium channels are represented by muscarinic cholinoreceptors

Ca"

Physiological reaction (e.g. contraction; exocytosis)

PIP2

Endoplasmic reticulum

Enzyme^ihosphorylation |

Enzyme^ihosphorylation |

Physiological reaction

Figure 2.6 Examples of second messenger systems:

Calcium signalling system. Ca2+ ions enter the cytoplasm either through plasmalemmal Ca2+ channels or through intracellular Ca2+ channels located in the membrane of endoplasmic reticulum. Once in the cytoplasm, Ca2+ ions bind to numerous Ca2+-sensitive enzymes (or Ca2+ sensors), to affect their activity and trigger physiological responses.

InsP3 signalling system. InsP3, produced following activation of metabotropic receptors/PLC, binds to InsP3 receptors (which are intracellular Ca2+ release channels) on the endoplasmic reticulum; activation of these receptors triggers Ca2+ release from intracellular stores and turns on the calcium signalling system.

cAMP signalling system. cAMP, produced following activation of metabotropic receptors/AC, binds to and activates a variety of cAMP-dependent protein kinases; these enzymes in turn phosphorylate effector proteins (e.g. plasmalemmal Ca2+ channels), thus affecting their function and regulating physiological cellular responses

(ion channels) or in the cell interior. Often, the plasmalemmal receptors and effector systems are linked through one or more second messengers.

Ionotropic receptors are essentially ligand-gated ion channels. Binding of a neurotransmitter to its receptor causes opening of the ion channel pore and generation of an ion flux, governed by the appropriate electrochemical driving force, determined by the transmembrane concentration gradient for a given ion and the degree of membrane polarization (Figures 2.4, 2.5). Activation of ionotropic receptors results in (1) a change in the membrane potential - depolarization or hyperpolarization, and (2) changes in intracellular (cytosolic) ion concentrations.

Metabotropic receptors are coupled to intracellular enzymatic cascades and their activation triggers the synthesis of various intracellular second messengers, which in turn regulate a range of intracellular processes (Figures 2.4, 2.5). The most abundant type of metabotropic receptors are seven-transmembrane-domain-spanning receptors. These receptors are coupled to several families of G-proteins, which control the activity of phospholipase C (PLC) and adenylate cyclase (AC) or guanylate cyclase (GC). These enzymes, in turn, control synthesis of the intracellular second messengers inositol-trisphosphate (InsP3) and diacylglycerol (DAG), cyclic adenosine 3',5'-monophosphate (cAMP) or cyclic guanosine 3',5'-monophosphate (cGMP). The G-proteins may be also linked to plasmalemmal channels, and often activation of metabotropic receptors triggers opening of the latter.

Second messengers are small (and therefore easily diffusible) molecules that act as information transducers between the plasmalemma and cell interior (Figure 2.6). The most ubiquitous and universal second messenger is calcium (Ca2+ ions), which controls a multitude of intracellular reactions, from exocytosis to gene expression. Other important second messengers include InsP3, cAMP and cGMP, cyclic ADP ribose and NAADP. Second messengers interact with intracellular receptors, usually represented by proteins/enzymes, and either up- or down-regulate their activity, therefore producing cellular physiological responses.

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