Metabotropic actions in the brain involves neurotransmitters such as serotonin, dopamine, and acetylcholine. Describe the broad principles of metabotropic communication, with particular reference to one of these neurotransmitters.

 

Metabotropic communication in the brain is initialized via neurotransmitters binding to specific postsynaptic receptors which indirectly induces an intracellular chemical signalling cascade. Of the approximate 100 billion neurons in the brain, only a quarter million receptors are present per type of the metabotropic neurotransmitter. In contrast to the rapid response of ionotropic communication, metabotropic actions are relatively slow. Often involving several intermediary proteins and chemical messengers along the signalling pathway. They also have more specific action than ionotropic communication which are responsible for all or nothing responses such as action potentials.

Metabotropic communication plays an important role in regulation of intracellular processes and balancing of cellular environments to keep them healthy and functioning optimally. They can trigger a multitude of subsequent effects on cellular function via initiating activation of protein signal intermediary pathways.

Metabotropic neurotransmitters work by binding to specific cell surface receptors which span the membrane and cause an alteration in their tertiary structure on the intracellular side of the membrane. This conformational change of the transmembrane receptor initiates a chain reaction of intracellular signalling sequences which are often complex and ultimately lead to a change in cellular activity.

The activity is often mediated by G-proteins, with the specific transmembrane cell receptor coupled to a G-protein at one of its intracellular domains. Metabotropic receptors are bound to an intracellular G-protein which upon receptor activation replaces GDP in its inactive form for GTP to become active and subsequently induces an enzymatic cascade which may trigger a variety of functions. Examples include opening an ion channel or altering its response relative to a voltage change across the cellular membrane (Barker, R.A et al. 2018).

Alternatively, the signal transduction mechanism initiated by the neurotransmitter-receptor binding can alter regulation of cellular protein as the particular signal cascade interacts with the DNA-protein complexes governing gene expression.

Serotonin can activate metabotropic communication pathways in the brain via more possible types of G-protein coupled receptors than are present for any other type of metabotropic neurotransmitter (Nichols & Nichols 2007). The serotonin receptors play a role in modulation of many brain functions such as those governing sleep and wake-fullness, mood and thermoregulation (Zheng 2018). Serotonin is a classical neurotransmitter, synthesized at the axon terminus of specific neurones from tryptophan via a 2-step enzymatic pathway and stored in vesicles. These fuse with the presynaptic axon terminus membrane when triggered by calcium ion influx caused by an action potential, releasing the serotonin into the synaptic junction where it diffuses across the synapse. It then binds to specific 5-HT postsynaptic receptors, which are all G protein coupled receptors (GPCR), except the 5HT-3 which is a ligand gated ion channel and is categorized as a nicotinic acetylcholine receptor (Berumen et al 2012). The serotonin GPCRs have seven transmembrane spanning hydrophobic domains and are encoded by 13 genes but can vary by more than 75% in genetic homology. To date, there are 7 families which collectively contain 14 distinct GPCRs, this excludes differential splicing of the same genes to create further subtypes (Nichols & Nichols 2007). The G-protein is composed of an alpha, beta and gamma subunit and upon binding of serotonin, the 5HT-GPCR alters its intracellular domain conformational structure which allows the ligated GDP to detach and be replaced by GTP at the site of the G-protein alpha subunit. Now activated, the alpha subunit of the G-protein detaches, complete with bound GTP which then triggers secondary messengers in a signalling cascade.

Serotonin cannot be reduced to either excitatory or inhibitory but has a neuromodulator function. There is a great diversity of excitatory or inhibitory effect on neurones depending on the pattern of serotonin receptors expressed by the cell and the type of cell. An example of the differentiation in neuromodulation are with 5HT1a receptors which one activated, hyperpolarize and thus increase inhibition of pyramidal neurons of the cerebral cortex, hippocampus and amygdala. However, 5HT2a receptors on the same neurons induce gradual membrane depolarization (Fröhlich 2016). Serotonin metabotropic activity in this case has opposing effects on the same cell: a feature common to metabotropic communication, allowing for fine tuning of cellular processes. Another advantage of metabotropic communication is that a single neurotransmitter can bind to its associated GPCR and activate an enzymatic pathway which opens multiple ion channels or multiplies a particular proteins synthesis. Effectively amplifying the initial signal by a huge factor. The proteins that are expressed via metabotropic communication may also be involved in the pathway e.g as the GPCR or an enzyme and their amplification further multiplies the resultant effect. Thus metabotropic actions are inherently neuromodulatory.

 

Barker, R.A., Cicchetti, F., Robinson, S.J. (2018) Neuroanatomy and Neuroscience at a Glance. Wiley Blackwell.

Nichols, D.E. & Nichols, C.D. (2007) Serotonin Receptors. Chem. Rev., 2008, 108 (5), pp 1614–1641

Berumen, L.C., Rodríguez, A., Miledi, R., García-Alcocer, G. (2012) Serotonin Receptors in Hippocampus. ScientificWorldJournal. 2012; 2012: 823493.

Zheng, W., (2018) Progress in Molecular Biology and Translational Science
Volume 154, Pages 1-176

Fröhlich, F. (2016) Network Neuroscience. Chapter 5 – Neuromodulators