Role of Non-adrenergic, Non-cholinergic Transmitters in the Autonomic Nervous System

The transmission of electrical signals from presynaptic junction to postsynaptic terminal that bring about action potentials through depolarization of cells between nerve and muscle are generally powered by neurotransmitters. The contraction and relaxation of smooth muscle cells of the visceral organs are under the control of autonomic nervous system. The neurotransmitters other than acetylcholine and noradrenaline of sympathetic and parasympathetic nervous systems play important roles in synaptic junction transmission, and these neurotransmitters are generally called Non-Adrenergic, Non-Cholinergic (NANC) neurotransmitters.  Currò D et al (1) stated that at around 1960s Burnstock and his team were the first set of neurophysiologists that discovered NANC neurotransmission and inhibitory junction potentials (IJP). The effect of NANC motor functions cut across cardiovascular, genitourinary, respiratory and most especially gastrointestinal system.  Joos GF (4) stated that most bronchodilation of the airway are as a result of inhibitory NANC transmitters, predominantly VIP and NO. Major NANC neurotransmitters with their inhibitory and excitatory roles in smooth muscle will be discussed in categories in this term paper as below:
Adenosine triphosphate (ATP)
According to Currò D et al (1), ATP as a neurotransmitter performs the inhibition of motor response in the proximal gastric region of the stomach. However, the relaxation effect of ATP particularly on the smooth muscle is usually temporary sustained, because ATP also simultaneously stimulate the release of contraction dependent prostaglandin in the body. This is a chemical agent that serves as an antagonist to the relaxation effect of ATP creating a short live effect of ATP on the smooth muscle. Additionally, cyclooxygenase inhibitors that hinder production of prostaglandin often time has little effect on ATP function. The effect of ATP is usually abridged by the ATP receptor antagonist including apamin, that block Ca2+, leading to influx of K+ into the cell with resultant hyperpolarization. However, except α-β-methylene ATP, apamin ( and not suramin) has no effect on the relaxation produced by electrical field stimulation (EFS) at the stomach proximal gastric region, especially EFS high frequency relaxation (2, 3). De Man JG (2) added that the inhibitory mediated effect of ATP occurs when ATP binds to purine receptors on the  intestinal smooth muscle and  nerve majorly P2Y1 and P2X1and 3 respectively. Nevertheless, Jenkinson KMet al(3) opined that this relaxant induced function of ATP can be blocked by action of P2-purinoceptor antagonist. Like wisely, Matsuda et al (5) explained the ATP mechanism of action that leads to its hyperpolarization of cells resulting in relaxation of smooth muscle. Firstly, ATP binds to purinergic G-protein receptor (P2Y), activates soluble apamin molecules. This chemical causes Ca2+ conduction through opening of K+ channels in the cell, activating adenylate cyclase enzyme and raising cyclic adenosine monophosphate (cAMP) level. Eventually, the cell is hyperpolarized with IJP leading to smooth muscle relaxation.
Mechanism of Action of ATP by Matsuda et al (5)
Vasoactive Intestinal Polypeptide (VIP) and Related Peptide
Currò D et al (1) described VIP, a sister of co-synthetized 27-amino-acid peptide histidine isoleucine (PHI), as a 28-amino-acid peptide that function in contraction-dependent relaxation of the gastric fundus. Peptides induced relaxation are not immediate, start after certain delay period and gradually increase in intensity; and they are long lasting contrary to latency deprived EFS induced relaxation that is autonomous of the frequency involved.  On the other hand, peptides play some major roles in the sustained length of relaxation induced by high frequency EFS of the proximal gastric region. In addition, high frequency EFS stimulation enhance the synthesis of VIP- like immunoreactivity (LI) from the stomach. In contrary, peptidergic component function becomes apparent for low frequency produced relaxation when there is an adequate and prolonged stimulation of neurons. However, the inhibitory motor function of VIP; low and intermediate frequency-EFS relaxation can be antagonized by anti-VIP sera including α-chymotrypsin and trypsin- peptidase (6). Matsuda et al (5) buttressed the fact that VIP serves as an inhibitory motor neurotransmitter principally in mesenteric motor neurons that leads to extended interval of relaxation of gastric smooth muscles.
VIP-Mechanism of Action
VIP transmitter which mixed with G-protein, binds to its VPAC-2 receptor on the fundus smooth muscle leading to increase in cAMP and activation of adenylate cyclase with resultant relaxation of smooth muscle. This relaxation effect is mediated when ATP-dependent K+ channel become activated with influx of Ca+ into the cell. The substance then prolongs the effect of voltage gated K+ channel leading to hyperpolarization, with no action potential generated. Eventually, the process potentiates inhibition and relaxation of gastric smooth muscle (5).
Also, Matsuda et al (5) stated that peptide inhibitory neurotransmitter including Pituitary Adenylate Cyclase-Activating Peptide (PACAP) participates as IJP in the relaxation of gastric smooth muscle. PACAP inhibitory effect often seen concurrently with VIP’s in the gastrointestinal tract (GIT)
PACAP-Mechanism of Action
PACAP neurotransmitter binds to its VCAP-1 and raise cAMP level, and PACAP type-1 receptor (PAC1). This joining increase influx of intracellular Ca2+, which then activates K+ channel, a apamin friendly channel (SKCa2+). The resultant efflux of K+ trigger hyperpolarization and relaxation of smooth muscle.
Mechanism of Action of VIP and PACAP
The figure explaining how the hyperpolarization, due to voltage gated Ca+ influx and K+ efflux, potentiates NANC VIP and PACAP inhibitory mediated effect on smooth muscle relaxation (5).
Joos GF(4) also emphasized that the nerves of upper and lower respiratory track including larynx and lung respectively are supplied with VIP and PACAP, functioning as vasodilator of bronchiolar tree. Moreover, innate immune cells including neutrophils and macrophages secrete VIP which specializes in decreasing the function of acquired immune cell including activated T-cells. This chemical simultaneously reduces the effect of proinflammatory cytokines, a signaling substance that increase inflammation, and increases anti-inflammatory cytokines in the circulatory system.
Nitric oxide (NO)
NO forms main NANC peripheral neurotransmitter of peripheral nervous system that ensure the immediate commencement of relaxation of GIT muscle and is well known as Endothelium-derived relaxing factor (EDRF). Currò D et al (1, 5) also point out the three main Ca2+ and calmodulin reliant isoforms of NO synthase (NOS) including endothelial’s (eNOS), neuronal’s (nNOS) and inductible’s (iNOS).  The relaxant mediated effect of NO is very diminutive due to its short half-life. The inhibitory function of NO often time demonstrated by quick onset of smooth muscle relaxation, as NOS inhibitors can eliminate the low frequency EFS relaxation and but has no power on relaxation secondary to high-frequency EFS. Even though NO works for beginning of gastric muscle relaxation, the relaxant function can be sustained by nonstop nitrergic nerve stimulation while peptidergic effects can leads to low or high frequency EFS. Additionally, Matsuda et al (5) shows that NO is produced from amino acid L-arginine by NOS, and nNOS isomer is more abundant in the neurons of GIT.
NO-Mechanism of Action.
NO originates from L-arginine asynthetized by the action of enteric nervous system (ENS) when gastric nerve is stimulated. This chemical which then lead to activation of soluble guanylate cyclase (sGC) and subsequent rise in cyclic guanosine monophosphate (cGMP). Thereafter, Protein kinase G acted upon by cGMP also activate K+ pathway, with increase Ca2+ influx that  eventually lead to hyperpolarization and relaxation of smooth muscle
Mechanism of Action of NO by Matsuda et al (5)
Irie K et al (6) also enunciated that the relaxation of smooth muscle is made possible by the action of endogenous NO, found in the myenteric plexus of the GIT, produced by L-arginine. However, an antagonist of NOS, majorly NG-nitro-L-arginine (L-NOARG) elicits some opposing effect; just as Tetrodotoxin (TTX) competes against the relaxant effect of ATP and VIP. More so, localized effect of endogenous NO in this plexus is often due to its short life span and this make it function as a neuromodulator, when secreted by action of [Met5] enkephalin (ENK), regulating the release of NANC neurotransmitters. Joos GF(4) expressed also that the nNOS isomer is predominant in the nerves of tracheobronchial pathway serving as inhibitory NANC neurotransmitter.
Carbon monoxide (CO)
Just like NO, CO is a gaseous neurotransmitter and chief hyperpolarizing factor that influence the relaxation of gastric smooth muscle. Oxidation of heme degradation through Nicotinamide adenide dinucleotide phosphate (NADPH) propelled by heme oxygenase (HO) leads to the production of CO endogenously. HO-2 Isoform produced CO in the GIT while HO-1 is mainly formed at the site of injury or inflammation. Activation of sGC raised the cGMP level, the increase K+ efflux results in hyperpolarization of cells and subsequent relaxation of the smooth muscle (5).
Mechanism of Action of CO by Matsuda et al (5)
Conclusively, relaxation of gastric smooth muscle is controlled by the functions of some NANC neurotransmitters including ATP, VIP, NO and CO among others through hyperpolarization of postsynaptic junction resulting in inhibition of action potentials. These chemicals often work in synergy as effect of one enhance the action of the other. Mainly, through activation of K+ channels that trigger hyperpolarization of cells resulting in smooth muscle inhibition (8)
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