Adrenergic nervous system
Adrenergic system is an evolutionarily ancient defence system, which consists of the organs and nerves in which catecholamines adrenaline (epinephrine) or noradrenaline (norepinephrine) act as neurotransmitter or neurohormone. Adrenaline and noradrenaline are released as neurotransmitters from sympathetic nerve endings and as neurohormones from adrenal medulla.
As neurotransmitter, noradrenaline is used in relatively few neurons in the brain, but receive input and send output to almost all parts of the brain and spinal cord. Outside of the CNS, noradrenaline is synthesized and released from postganglionic neurons of the sympathetic nervous system. Noradrenergic neurons are clustered in the synpathetic ganglia next to the spinal column. Noradrenaline is a major neurotransmitter in the peripheral nervous system. Noradrenaline is involved in regulation of cognition, arousal, attention, sleep-wake cycles, stress, memory formation, emotions, synaptic plasticity, sensory processing, cardiovascular function, and neuroendocrine signalling. Degeneration of the noradrenergic system is typical in neurodegenerative diseases such as PD, AD, and HD (Marien et al., 2004; Holland et al., 2021).
Synthesis of noradrenaline begins with hydroxylation of L-phenylalanine to L-tyrosine and then, in a rate-limited step catalysed by tyrosine hydroxylase (TH), into dihydroxyphenylalanine (L-DOPA). TH is considered as a marker of sympathetic neurons. DOPA decarboxylase (AADC) converts DOPA into dopamine, which is taken up into synaptic vesicles by vesicular monoamine transporter 2 (VMAT2). Dopamine is converted into noradrenaline by dopamine β-hydroxylase (DβH) in the synaptic vesicles of noradrenergic and adrenergic neurons. Synaptically released noradrenaline is taken back into presynaptic neurons by noradrenaline transporter (NAT/NET). Extraneuronal monoamine transporters (EMTs), mainly organic cation transporter 3, mediate low level sequestering of noradrenaline in most tissues. Noradrenaline is metabolized by MAO-A and MAO-B, and COMT.
The noradrenic neurons exhibit both tonic and phasic firing. The basal (tonic) activity makes up the most of synaptic noradrenaline. Presynaptic autoreceptors inhibit synaptic release. Noradrenergic neurons release noradrenaline also from non-synaptic sites; this "volume transmission" leads to broad spatial and temporal effects.
Metaraminol is a synthetic noradrenaline analogue that shares the same neuronal uptake, storage, and release pathways, but is not metabolized by COMT and MAO.
Synthesis of adrenaline follows the same route as synthesis of noradrenaline. In the central adrenergic neurons and in adrenal chromaffin cells, the synaptic vesicles contain phenylethanolamine N-methyltransferase (PNMT), which methylates noradrenaline to adrenaline.
Adrenergic receptors (adrenoceptors, ARs) belong to the superfamily of transmembrane G protein-coupled receptors. The two main types, α- and β-adrenoceptors are classified into subtypes α1A, α1B, α1D, α2A, α2B, α2C, and β1, β2 and β3. Adrenaline and noradrenaline act as an agonist of all adrenoceptor subtypes, with different affinity: α1AR and β3AR favour noradrenaline over adrenaline; β2AR favours adrenaline over noradrenaline; and α2AR and β1AR usually favour both equally. Adrenoceptors located on the catecholaminergic neurons are referred to as autoreceptors, and those located on non-adrenergic cells as heteroreceptors.
ARs can go through homo- and heterodimerization, even with other receptor types. Agonist binding to ARs will lead to internalization of the receptor, which does not only desensitize ARs, but can also increase AR signalling.
In CNS, α2AAR is widely distributed, constituting about 90% of the α2ARs, while α2CAR (10% of total) is expressed mainly in the ventral and dorsal striatum and hippocampus (Fagerholm et al., 2008; Uys et al., 2017). Specific radiopharmaceuticals for the α2AARs are under development (Krzyczmonik et al., 2019). Density of available α2CARs in the brain can be quantified using [11C]ORM-13070, and the radiopharmaceutical can also be used to detect increase in synaptic noradrenaline levels (Finnema et al., 2015; Lehto et al., 2016).
In peripheral tissues α-adrenoceptors located on vascular smooth muscle cells mediate vasoconstriction. α2-adrenoceptors are also found in renal, pancreatic, hepatic, and adipose tissues (Scheinin & Hietala, 1989). Atipamezole is a specific antagonist for α2-ARs. [11C]yohimbine is an antagonist radioligand which binds with high specificity to all α2-AR subtypes (Jacobsen et al., 2006), and can be used in brain PET for occupancy studies (Laurencin et al., 2021).
In rodent brown adipose tissue (BAT) β3ARs are highly expressed, while in human BAT β2ARs are dominant. The β2AR and β3AR agonists increase [18F]FDG uptake (Cypess et al., 2015; Baskin et al., 2018; Straat et al., 2023) by inducing UCP1 expression, and can increase resting metabolic rate (Marlatt & Ravussin, 2017).
Cardiac and pulmonary β-AR density has been measured using [11C]CGP12177 (Delforge et al., 1991; Ueki et al., 1993; Hayes et al., 1996; Qing et al., 1996 and 1997; Ohte et al., 2012; Bernacki et al., 2016; Goto et al., 2021).
- Noradrenaline transporter
- Dopaminergic system
- Serotonergic system
- Cholinergic system
- Glutamatergic system
- Endocannabinoid system
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Tags: Adrenoceptors, Adrenaline, Noradrenaline, Catecholamines, NAT, Autonomic nervous system
Updated at: 2023-03-08
Created at: 2017-10-07
Written by: Vesa Oikonen