How neurotransmitters regulate body.
Central nervous system (the brain and spinal cord) governs all life activities of the body by regulating functions of the cells that are linked to the brain and spinal cord via peripheral central system (nerves). The brain "feels" the body via afferent (sensory) fibers of peripheral nerves and exerts its functional influence on all cells of the body via efferent nerve fibers of the same nerves. Let's talk about how the brain and spinal cord use their efferent neural ways, conducting impulses outwards the central nervous system, to affect each individual cell of the body. The thing is that distal ends of efferent neuronal fibers of nerves have structures called synapses. "The nervous system has evolved various kinds of synapses, including those between axon terminals and dendrites, cell bodies, muscles, other axons, and even other synapses, as well as those that release their chemical transmitters into extracellular fluid or into the blood and those that connect dendrites to other dendrites" (Kolb B. & Wishaw I. Q., 2003). According to this, the very different synapses of the body convert a neuronal signal into the release of neurotransmitters. Indeed: "Synapses are the junctions where neurons release a chemical neurotransmitter that acts on a postsynaptic target cell, which can be another neuron or a muscle or gland cell" (Lodish H. et al., 2003). It means that the neuronal signals, going outwards from the brain and spinal cord, are converted in chemical signals that go to the target cells. So, the synapses of efferent nerves convert and transfer efferent signals in one direction only: from the brain and spinal cord to the postsynaptic target cells. Do the postsynaptic target cells include neuronal, muscle and gland cells only? How about other kinds of cells? Are they targets for neurotransmitters produced and released by the peripheral synapses? The answer is "yes". According to the same authors (Lodish H. et al., 2003), neurotransmitters affect postsynaptic target cells mostly via paracrine signaling (locally). This means that any cells in close proximity from postsynaptic terminal are affected by the neurotransmitter release from the synapse of the efferent fiber of nerve. To be affected by the neurotransmitters, the cell should have specific receptor(s) to these molecules. Let's summarize this information. Any efferent signal from the brain or spinal cord is converted in the synapses into the neurotransmitter. The neurotransmitter, released locally into the tissue and capillary vessels, should affect the cells located nearby and having specific receptors for this neurotransmitter. The signal from brain or spinal cord to the target cell goes through the following simplified* chain of structures and events: brain or spinal cord → efferent nerve way* → synapse → neurotransmitter release → receptors for neurotransmitter on the target cell → neurotransmitter's effect on the target cell. So, if the cell has the specific receptors for neurotransmitters, these receptors supposed to be employed in most effective, specific manner. The nervous system is their most specific "user": the signal sent from the brain or spinal cord via efferent nerve fibers achieves as neurotransmitters its target cell. This concept has been recognized and proved in the scientific literature; extensive amount of papers directly point out the role of neurotransmitter receptors expressed on the cells of various tissues and organs of the body in regulation of these cells, tissues and organs by the central nervous system. Here we put some quotes from the peerreviewed papers that illustrate and confirm this concept. Let's start from the cells of the immune system. "Lymphocytes and macrophages have receptors for a vast number of hormones and neuropeptides; hormones and neuropeptides can alter the functional activity of immune system cells"(Falaschi P. et al., 1994). "Accessory immune cells and lymphocytes have membrane receptors for most neurotransmitters and neuropeptides. These receptors are functional, and their activation leads to changes in immune functions"(Dantzer R. & Wollman E.E., 2003). "The concept of nerve-driven immunity recognizes a link between the nervous and the immune system. GABA is the main inhibitory neurotransmitter in the brain, and receptors activated by GABA can be expressed by immune cells" (Bhandage A.K. et al., 2015). According to these and other data, lymphocytes, monocytes and macrophages express the receptors for most neurotransmitters, these receptors on immune cells are functional, and their activation regulates immunity. Let's see a few examples on female reproductive system. Activation of muscarinic receptors in the left ovary through a stimulatory neural signal (coming via the vagus nerve from the hypothalamus) is required for ovulation (Cruz M.E. et al., 2015). "...The peripheral neural pathway ... represents an additional mechanism to control luteal function (producing progesterone) in addition to the classical endocrine regulation" (Ghersa F. at al., 2015). "Tachykinins are neuropeptides that are widely distributed in the body and function as neurotransmitters and neuromodulators" (Goto T. & Tanaka T. 2002). "The peptides of the tachykinin family participate in the regulation of reproductive function acting at both central and peripheral levels" (Pinto F.M, et al., 2015). Just like in the examples above, the brain and spinal cord, via synapses and neurotransmitters of peripheral nerves, regulates activity of bone cells. "...Nerve cells which exist in and around bone such as periosteal and bone marrow build a close relationship with bone cells... Central nervous system governs bone tissues via peripheral nervous system and neurotransmitters or cytokines play a role for the communication between bone and nerve in the last decade"(Sato T., 2016). "...Neuropeptides and their receptors regulate osteoblast and osteoclast function in vivo"(Elefteriou F., 2008). "...Neurotransmitter glutamate is also found in the periphery in an increasing number of nonexcitable cells. ...Glutamate can regulate a broad array of peripheral biological responses... The roles of glutamate signaling pathways in these regions (head and neck) are manifold and include ... periodontal bone production, skin and airway inflammation, as well as salivation..."(Haas H.S. et al., 2010). A nice example of central nervous regulation of gland cells via peripheral nervous system is the regulation of thyroid gland cells (thyrocytes). "Activation of the central a-adrenergic mechanisms increases the release of thyroid-stimulating hormone of pituitary mainly due to the stimulation of its secretion. ...Acetylcholine and other cholinomimetics inhibit the functional activity of thyrocytes with the participation of muscarinic receptors. ...Serotonin can inhibit the secretion of thyrotropin by the pituitary gland, but has a direct stimulatory effect on thyrocytes. This stimulatory effect is mediated by the serotonin 5-HT2 receptors" (Lychkova A.E., 2013). Regarding to the adrenal gland, it has been shown that activation of central neurons of hypothalamus "facilitates epinephrine release by increasing sympathetic drive to adrenal chromaffin cells during hypoglycemia" (Korim W.S. et al., 2016). There has been described the role of activation parasympathetic and sympathetic nerves (Taborsky G.J. et al., 2012) and acetylcholine receptors on the adrenal glands (LaGamma E.F. et al., 2014) in regulation of glucagon response in these cells. Additionally to the data that illustrate and confirm the role of neurotransmitters in nervous regulation of the cells of peripheral tissues and organs above, there is an extensive amount of highly relevant papers that provide evidence that various cells of the human body express the receptors for various neurotransmitters, and those cells are functionally activated by the transmitters. Since 80s it has been recognized that neurotransmitter GABA and its receptor are expressed and involved in synaptic transmission in various peripheral tissues and organs including the intestine, stomach, pancreas, fallopian tube, uterus, ovary, testis, kidney, urinary bladder, lung, and liver (Erdö S.L. & Wolff J.R., 1990). These findings were just confirmed by later studies. GABA and its receptors are found in the cells of female reproduction system (Dai H. et al., 2016; Zhou Z. et al., 2010), the cells of lungs (Xiang Y.Y. et al., 2007; Mizuta K. et al., 2008); dental cells (Konermann A. et al., 2016), immune cells (Bhandage A.K. et al., 2015). The similar pool of data was obtained for another neurotransmitter acetylcholine. Expression of acetylcholine receptors was found the cells of reproductive system (Bschleipfer T. et al., 2012); renal cells (Kim C.S. et al., 2016); the cells of connective tissues (bone, cartilage) and bone marrow cells (Guo J. et al., 2014). According to the abundant peer-reviewed information in the scientific literature (that we covered here just insignificantly), not only the cells of neuronal, muscular and gland tissues, but all the cells of other tissues and organs in the human body are regulated by the central nervous system (the brain and spinal cord) via the local release of neurotransmitters, produced by the synapses on endings of the efferent nerve fibers.
References
Bhandage AK, Hellgren C, Jin Z, Olafsson EB, Sundström-Poromaa I, Birnir B. Expression of GABA receptors subunits in peripheral blood mononuclear cells is gender dependent, altered in pregnancy and modified by mental health. Acta Physiol (Oxf). 2015 Mar;213(3):575-85. Bschleipfer T, Weidner W, Kummer W, Lips KS. Does bladder outlet obstruction alter the nonneuronal cholinergic system of the human urothelium? Life Sci. 2012 Nov 27;91(21-22):1082-6
Cruz ME, Flores A, Alvarado BE, Hernández CG, Zárate A, Chavira R, Cárdenas M, ArrietaCruz I, Gutiérrez-Juárez R. Ovulation requires the activation on proestrus of M muscarinic receptors in the left ovary. Endocrine. 2015 Aug;49(3):809-19.
Dai H, Hao C, Huang X, Liu Z, Lian H, Liu C. Different transcriptional levels of GABA(A) receptor subunits in mouse cumulus cells around oocytes at different mature stage. Gynecol Endocrinol. 2016 Jun 26:1-5
Dantzer R, Wollman EE. Relationships between the brain and the immune system. J Soc Biol. 2003; 197(2):81-8
Elefteriou F. Regulation of bone remodeling by the central and peripheralnervous system. Arch Biochem Biophys. 2008 May 15;473(2):231-6.
Erdö SL, Wolff JR. gamma-Aminobutyric acid outside the mammalian brain. J Neurochem. 1990 Feb;54(2):363-72. Review.
Falaschi P, Martocchia A, Proietti A, Pastore R, D'Urso R, Barnaba V. Neuroendocrinoimmunology. Ann Ital Med Int. 1994 Apr-Jun;9(2):96-9
Ghersa F, Burdisso J, Vallcaneras SS, Fuentes F, de la Vega M, Delgado SM, Telleria CM, Casais M. Neuromodulation of the luteal regression: presence of progesterone receptors in coeliac ganglion. Exp Physiol. 2015 Aug;100(8):935-46.
Goto T, Tanaka T. Tachykinins and tachykinin receptors in bone. Microsc Res Tech. 2002 Jul 15;58(2):91-7. Review.
Guo J, Wang L, Xu H, Che X. Expression of non-neuronal cholinergic system in maxilla of rat in vivo. Biol Res. 2014 Dec 17;47:72
Haas HS, Linecker A, Pfragner R, Sadjak A. Peripheral glutamate signaling in head and neck areas. Head Neck. 2010 Nov;32(11):1554-72.
Kim CS, Choi JS, Joo SY, Bae EH, Ma SK, Lee J, Kim SW. Nicotine-Induced Apoptosis in Human Renal Proximal Tubular Epithelial Cells. PLoS One. 2016 Mar 30;11(3):e0152591
Kolb, B. & Wishaw, I. Q. (2003). Fundamentals of Neuropsychology (6th Edition). Worth Publishers: New York. p.163
Konermann A, Kantarci A, Wilbert S, Van Dyke T, Jäger A. Verification of γ-Amino-Butyric Acid (GABA) Signaling System Components in Periodontal Ligament Cells In Vivo and In Vitro. Cell Mol Neurobiol. 2016 Feb 1
Korim WS, Llewellyn-Smith IJ, Verberne AJ. Activation of Medulla-Projecting Perifornical Neurons Modulates the Adrenal Sympathetic Response to Hypoglycemia:Involvement of Orexin Type 2 (OX2-R) Receptors. Endocrinology. 2016 Feb;157(2):810-9.
LaGamma EF, Kirtok N, Chan O, Nankova BB. Partial blockade of nicotinic acetylcholine receptors improves the counterregulatory response to hypoglycemia in recurrently hypoglycemic rats. Am J Physiol Endocrinol Metab. 2014 Oct 1;307(7):E580-8.
Lodish H., Berk A., Matsudaira P., Kaiser C.A., Krieger M., Scott M. P., Zipursky L., Darnell J. Molecular Cell Biology 5th Edition. New York: W. H. Freeman, 2003.
Lychkova AE. [Nervous regulation of thyroid function]. Vestn Ross Akad Med Nauk. 2013;(6): 49-55. Review.
Mizuta K, Osawa Y, Mizuta F, Xu D, Emala CW. Functional expression of GABAB receptors in airway epithelium. Am J Respir Cell Mol Biol. 2008 Sep;39(3):296-304
Pinto FM, Bello AR, Gallardo-Castro M, Valladares F, Almeida TA, Tena-Sempere M, Candenas L. Analysis of the Expression of Tachykinins and Tachykinin Receptors in the Rat Uterus During Early Pregnancy. Biol Reprod. 2015 Aug;93(2):51. Sato T. "Osteo-neural" related factors - bridge over bone homeostasis. Clin Calcium. 2016 Aug;26(8):1127-34.
Taborsky GJ Jr, Mundinger TO. Minireview: The role of the autonomic nervous system in mediating the glucagon response to hypoglycemia. Endocrinology. 2012 Mar;153(3):1055-62.
Xiang YY, Wang S, Liu M, Hirota JA, Li J, Ju W, Fan Y, Kelly MM, Ye B, Orser B, O'Byrne PM, Inman MD, Yang X, Lu WY. A GABAergic system in airway epithelium is essential for mucus overproduction in asthma. Nat Med. 2007 Jul;13(7):862-7.
Zhou Z, Sun H, Li X, Li Y, Zhao S, Zhang D, Yao Z, Li J. A local GABAergic system is functionally expressed in human fallopian tube. Biochem Biophys Res Commun. 2010 Jul 23;398(2):237-41.