General Overview of Signalling in the Nervous System
2.2 Intracellular signalling
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 plasmalemmalreceptorsthat sense the external stimulus, and effector systems, which can be located either within the plasmalemma
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 depolar- ization 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
18 CH02 GENERAL OVERVIEW OF SIGNALLING IN THE NERVOUS SYSTEM
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. GABAAand glycine receptors; activation of these receptors in neurones causes Cl−influx, hence hyperpolarizing and inhibiting the cells, but in glia (and immature neurones) their acti- vation 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 phospholipaseC (PLC), adeny- late 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
2.2 INTRACELLULAR SIGNALLING 19
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 retic- ulum. 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
20 CH02 GENERAL OVERVIEW OF SIGNALLING IN THE NERVOUS SYSTEM
(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 gener- ation 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.