Catecholamine Biosynthesis in the Adrenal Medulla
In response to stress, the sympathetic nervous system affects a variety of target organs, including the adrenal medulla. Specifically, the splanchnic nerve stimulates the adrenal medulla to release catecholamines (epinephrine and norepinephrine) through its release of acetylcholine and PACAP (pituitary adenylate-cyclase activating polypeptide) onto nicotinic acetylcholine receptors and G-protein coupled receptors, respectively, on chromaffin cells. The following article aims to summarize catecholamine biosynthesis in the chromaffin cells, as well as the regulatory mechanisms for their synthesis and secretion.
Parasympathetic vs Sympathetic Innervation
The human nervous system can be organized into the central nervous system and the peripheral nervous system, the central nervous system consisting of the brain and spinal cord. The peripheral nervous system can be broken down into the autonomic nervous system (involuntary control) and the somatic nervous system (voluntary control). The parasympathetic and sympathetic nervous systems are two of the three divisions of the autonomic nervous system (the third being the enteric system). The sympathetic nervous system is commonly referred to as the “flight-or-fight” system, whereas the parasympathetic nervous system is known as the “rest-and-digest” system. Contrary to common wording that indicates when one system is activated, the other is “off”, they are both constantly “on” and responding to external and internal signals. The neuroendocrine systems of the body are constantly integrating various signals and responding to regulatory feedback mechanisms.
The parasympathetic nervous system, whose long, myelinated preganglionic neurons originate in the brainstem and sacral segment of the spine (S2-S4) and synapse onto postganglionic neurons near the effector organ, constricts pupils, stimulates salivary gland secretion, slows the heart rate, and stimulates stomach & intestinal digestion, amongst other things. The preganglionic neurons release acetylcholine onto ligand-gated nicotinic acetylcholine receptors (which is the same for sympathetic preganglionic neurons), and the postganglionic neurons of the parasympathetic nervous system release acetylcholine onto G-protein coupled muscarinic acetylcholine receptors, leading to the systemic effects above.
The sympathetic nervous system originates in the thoracic and lumbar regions of the spinal cord (T1 through L2). Its preganglionic neurons are often shorter and synapse onto the paravertebral sympathetic chain, releasing acetylcholine onto nicotinic acetylcholine receptors there. The sympathetic nervous system affects target organs in multiple ways, such as dilating the pupils, inhibiting salivary gland secretion, accelerating the heart rate, and inhibiting stomach & intestinal digestion. This is achieved by the release of norepinephrine from postganglionic neurons onto various G-protein coupled adrenergic receptors on the target organs.
Sympathetic Innervation of the Adrenal Medulla
In regards to the sympathetic innervation to the adrenal medulla (which receives only sympathetic innervation, not parasympathetic innervation), the preganglionic neurons travel through the celiac ganglion without synapsing there, synapsing instead onto the adrenal medulla, which stimulates the release of stored catecholamines from chromaffin cells into circulation. The preganglion releases acetylcholine onto ligand-gated nicotinic acetylcholine receptors (as in parasympathetic and other sympathetic preganglionic synpases), and the adrenal medulla acts as a modified postganglion, which makes sense given its arising from neural crest cells during embryonic development. The sodium entry associated with the acetylcholine binding to the nicotinic acetylcholine receptors leads to a depolarization of the chromaffin cells of the adrenal medulla (modified postganglion), allowing the opening of voltage-dependent calcium channels. When calcium enters the cell, it binds to calmodulin, which facilitates the exocytosis of vesicles containing catecholamines by mediating the v-snare finding the t-snare. The following section describes how catecholamines are synthesized and stored in the vesicles that are exoctyosed upon sympathetic signaling.
Biosynthesis of Catecholamines in Chromaffin Cells
The adrenal medulla consists of chromaffin cells, which are the cells responsible for the synthesis and secretion of epinephrine and norepinephrine into the circulation. Although norepinephrine acts primarily as a neurotransmitter, it also acts as a hormone within blood circulation when released from chromaffin cells. Because catecholamines can be synthesized at an earlier time and stored in vesicles (unliked steroid hormones, such as cortisol, which are not stored and require synthesis and diffusion upon arrival of a signal), their release into the circulation is rapid. Epinephrine release accounts for the quick, initial response to stress.
Within the cytosol of a chromaffin cell, tyrosine (which entered the cell through an amino acid transporter in the plasma membrane) becomes DOPA by the enzyme tyrosine hydroxylase (TH). DOPA is converted to dopamine in the cytosol by DOPA decarboxylase, which releases carbon dioxide. Dopamine can be carried into a vesicle where the catecholamines will be stored with chromogranin until the vesicle is exocytosed. It is carried into the vesicle by a vesicular monoamine transporter (VMAT), which is an anti-port that couples the removal or entry of amines with protons moving in the opposite direction. The vesicle also contains an active proton pump to maintain the proper proton gradient. Once inside the vesicle, dopamine becomes norepinephrine by dopamine B-hydroxylase. Norepinephrine will either be stored as norepinephrine-sulfate or will leave through VMAT, becoming epinephrine in the cytosol by phenylethanolamine N-methyltransferase (PNMT). Epinephrine enters the vesicle through VMAT, where it is stored as epinephrine-sulfate. When the vesicle is exocytosed, the catecholamines are released, along with the chromogranin it is stored with. Despite the fact that the chromaffin cells release 80% epinephrine and 20% norepinephrine, norepinephrine levels are still higher within the circulation because of the continuous release of norepinephrine as a neurotransmitter.
Biological Functions of Catecholamines
Upon their release from the adrenal medulla and entry into circulation, epinephrine and norepinephrine bind to adrenergic receptors on multiple tissues. Different adrenergic receptors have varying effects on their target tissue and different sensitivities/affinities to epinephrine versus norepinephrine. Despite skeletal muscle being part of the somatic nervous system and not receiving sympathetic innervation, it can respond to sympathetic nervous system signals because of circulating catecholamines that can bind to its adrenergic receptors. Because they are released in response to stress, catecholamines’ primary function is to maintain blood glucose and increase the availability of alternative fuel sources (i.e. fatty acids). As a result of catecholamines binding to adrenergic receptors, gluconeogenesis is increased in the liver, glucose uptake is decreased in skeletal muscle and adipose tissue, glycogenolysis is increased in skeletal muscle and adipose tissue, and there is an increase in lipolysis and B-oxidation in the liver, skeletal muscle, and adipose tissue, amongst many other things.
Modulations of the Synthesis and Secretion of Catecholamines
The constant and complex regulation of the endocrine system includes mechanisms to increase or decrease both the synthesis and secretion of hormones, including catecholamines. High calcium in the chromaffin cell binding to calmodulin leads to high activity levels of calcium/calmodulin-dependent protein kinase (CaMK), which leads to an increased phosphorylation of TH (covalent regulation), thereby increasing the activity of TH, converting more tyrosine into DOPA. However, to counteract that, high levels of DOPA in the cell allosterically inhibit TH activity, as opposed to high levels of tyrosine, which allosterically stimulate TH. One way to modify the secretion of catecholamines is to inhibit exocytosis and the mediation of the v-snare finding the t-snare: epinephrine and norepinephrine can signal in an autocrine fashion, binding to G-protein coupled adrenergic receptors on chromaffin cells, inhibiting exocytosis through the secondary messenger cascade associated with the GPCR. Cortisol secretion via HPA stimulation can lead to increased transcription/translation in the nucleus by the binding of phosphorylated-CREB to CRE, thereby increasing the concentration of PNMT and VMAT. PACAP, secreted by sympathetic preganglions along with acetylcholine, can bind to G-protein coupled receptors on the plasma membrane of the chromaffin cell, initiating a secondary messenger cascade that increases the activity of PKA to phosphorylate TH, as well as travels to the nucleus to increase the transcription/translation and concentration of TH.
The complexity of the neuroendocrine system should be noted, in particular the meticulous and redundant regulation of hormone synthesis and secretion. Psychological responses can have systemic downstream effects, providing further evidence that physiology often follows psychology. The role of mental and emotional wellbeing in physical health should not be understated. The inner workings of the brain are still a great mystery, and it is sympathetic nervous system activation that begins the large sequence of events described above. The inter-connectivity of various organs in the human body is baffling and a puzzle far from being fully solved.