Co-transmission - Coursework Example

Name : xxxxxxxxxxx Institution : xxxxxxxxxxx Title : Co-transmission Tutor : xxxxxxxxxxx Course : xxxxxxxxxxx @2010 Co-transmission A co-transmitter is a substance which transmits messages to the cells that surround it or to the same nerve when the nerve releases it, hence modulating their roles. Co-transmission therefore can be defined as the releasing of a substance (co-transmitter) together with primary neurotransmitter from the nerve endings for the modification of the co-transmitter, for instance the vasoactive intestinal peptide works like a co-transmitter with the acetylcholine in the cholinergic synapses. The researchers, even as early as 1970s, have always considered co-transmission as a zealous curiosity and which plays a given role in the unusual nerve stimulation responses, visible in some smooth muscles which are innervated autonomically. Currently various researchers have agreed with the view of cotransmission as the rule and not the neurotransmission exception (Varoqui, 2002). Autonomic pharmacology The first neurotransmission studies which were done by Sir Henry Dale and his team around 1930s. His team got involved in a deeper investigation of ergot alkaloids’ pharmacology and the study on the effects and characteristics of simple bases like histamine and tyramine. Pituitary extracts’ oxytocic action was later discovered by him. He also continued working on the histamine action and this led to condition of shock and anaphylaxis being investigated, where acetylcholine was discovered as certain ergot extract’s constituent and that it had same effects to various organs’ parasympathetic nervous system. It was later discovered by Otto Loewi that a substance released from vargus nerve’s electrical stimulation affected heartbeat changes, and after further developments on the work by Dale, the substance was discovered to be acetylcholine, thereby firmly established that the noradrenaline was used by the sympathetic nerves as their neurotransmitter while the acetylcholine was used by the parasympathetic nerves as their neurotransmitter, this is in addition to the discovery that chemical and electrical stimuli play an important role in nerve action (Sneddon & Machalay, 1992). Dale then proposed that, in consideration of a given neurone’s metabolic unity, the same transmitter would be released by all the nerve’s terminals. While the involvements of many autonomic nerve co-transmitters have not been precluded in this, other significant texts believed in the idea of one transmitter being involved. However much it was perceived as the reasonable interpretation of the data that was available during Dale’s era, it became a practice that may have hindered interpretation of other experimental findings which followed. The one nerve-one transmitter principle was very close to universal acceptance and lasted in this position for a longer period (Vogt, 1969). Co-transmission was later considered as a vital concept by various investigations. These investigations included the functional studies and histochemical studies. In functional studies, the responses of some preparations of smooth muscles that were isolated failed to show the expected cholinergic or classical noradrenergic nerve responses. The histochemical studies showed more than two co-localisations in every nerve terminal. Early evidence Between 1950 and 1960 there was work done on co-transmission in the autonomic nerves. This stimulating work was done by Rand and Burn and it provided a ‘false start’ to the co-transmission concept. According to them, acetylcholine was released by the noradrenergic neurones, and then the acetylcholine worked prejunctionally in the promotion of the noradrenaline release (Sneddon& Machalay, 1992). Even though it is no longer viewed as tenable, this hypothesis significantly challenged the previous idea of autonomic transmission as being a simple process that had a single transmitter. Around 1960s, there was availability of selective as well as new drugs with the autonomic neurotransmission pharmacology undergoing deep investigation. Burnstock and his Australian team realized that responses of several preparations of the smooth muscles that were isolated couldn’t have there explanation on the basis of classical noradrenergic as well as cholinergic mechanisms thereby using ‘non-adrenergic, on-cholinergic’(NANC) nerves in indication of the current autonomic nerve class. They then worked on identifying the neurotransmitter of NANC of which they identified as the Purine adenosine 5’-triphosphate (ATP) around 1970s. The review of the topic which contained evidence for the support of ‘purinergic nerves’ was later presented in 1972. Therefore the hypothesis of the purinergic nerves played a very significant role in reinforcing investigations on the idea of autonomic nerve co-transmission (Burnstock, 1972). Co-transmitter hypothesis The early co- transmission proof happened during the time when different studies doing the investigation of the isolated smooth muscles’ mechanical responses to the NANC nerve stimulation started being reassessed basing on the co-transmission possibility. The rodents’ isolated vas deferens was among the most important preparations which unveiled more details on co-transmission. Result from various vas-deferens studies with details on the mechanical responses made the evidence even stronger, thereby strengthening the idea that the ATP as well as the noradrenaline function as co-transmitters in mediating the muscle’s complicated mechanical responses to its sympathetic innervation stimulation. In the sympathetic nerves, ATP has also been proved to be a co-transmitter with nor-adrenalin while acting the same role on the parasympathetic nerves using the acetylcholine, this happens in several tissues that are autonomically innervated for instance the urinary bladder’s smooth muscle and also in the smooth muscle of the vascular. Currently there is substantial evidence on the putative co-transmitter co-localisation in central nervous system, nerves of the somatic motor, peripheral autonomic ganglia, and the sensory neurones, both in mammals as well as invertebrates, amphibians, crustaceans, birds and also insects (Kupferman, 1991). Synthesis, storage and release Blaschko and his team did some work in early 1950s which revealed the noradrenaline’s synthetic pathway as well as the high-concentration existence of the ATP, which is also stored with the noradrenaline in the adrenal medulla’s chromaffin granules. It was also indicated that the vesicles of the noradrenergic nerves was not only able to store but also release ATP, noradrenaline included. This was not considered as evidence until later on. Many researchers had always regarded the ATP presence as the substance for the packaging and also storage of noradrenaline within the sympathetic vesicle. There exists various biochemical estimations of the quantity of noradrenaline to the ATP which is stored in the sympathetic vesicles with ranges from 4:1 to the most current and reliable estimation of 20:1 up to 50:1. After the discovery of the ATP as the noradrenergic nerve terminal constituent, it became clear that its storage was also together with the acetylcholine in the terminals of the cholinergic nerves (Silinsky&Hubbard, 1973). During 1970s, due to considerable impetus on co-transmission, there were significant advances since the immunochemical methods were applied in the localisation of the number of putative peptide neurotransmitters that were continuously increasing. Currently there is a great variety of literature documenting many examples of peptide co-localisation in all neurones (Furness, 1989). However, a consistent pattern giving more insight on the importance of functions on the various peptide co-existences has been found. Some neurones have been identified to have co-localisation of more than four peptides. For instance, the guinea-pig’s secretomotor neurones in the small intestines has an immunoreactivity to the cholecystokinin (CCK), calcitonin gene-related peptide(CGRP), neuropeptide Y (NPY), galanin (GAL) and somatostanin.The guinea-pig skin’s sensory neurones have been recognised to positively stain for the cholecystokinin, calcitonin gene-related peptide, galanin, dynorphin(DYN) as well as substance P. The vasodilator neurones of the uterine arteries of guinea -pig have also been realized to have dynorphin, neuropeptide Y, somatostanin and the vasoactive intestinal peptide (VIP). The co-storage of a single or a number of peptides together with the non-peptide neurotransmitters seem like a vital combination. Neuropeptide Y is a better example of this, considering that it is among the neuropeptides which are abundant and found within the central nervous system as well as the peripheral neurones, where it exists with the noradrenaline in combination (Lundberg, 1990). However, there is co-existence of noradrenaline and ATP (non-peptide neurotransmitters) in the vas deferens of guinea-pig. The neocortical neurones also have vasoactive intestinal peptide and also the acetylcholine in the central nervous system. There is some functional significance in the idea that while the synthesis of Purine adenosine 5’-triphosphate (ATP), acetylcholine and noradrenalin happens locally in the nerve terminals, the production of the neuropeptide always gets restricted to ribosomes in the body of the nerve cells. The peptide then gets transported in the vesicles from cell soma to nerve terminals through axonal transport which is a slow process. This signifies that there is some little amount of peptide which could be readily released, while the stores will take a considerably longer time to replace after nerve activity burst. There is an indication by biochemical estimations that the concentration of the peptides that are stored in nerves are many orders of the magnitude which is lower than classical co-transmitter concentration. The peptides, therefore, generally seem to be having a high receptor affinity hence functioning at a very low concentration compared to the conventional co-transmitters, mainly becoming active in the range of nanomolar, in comparison with micromolar concentrations which are associated with the non-peptide transmitters (Whittaker, 1972). Storage vesicles: subpopulations Occurrence of co-transmitters as packaged in synaptic vesicles’ homogeneous population or occurrence of various transmitters in distinct vesicle subpopulations is a vital factor of co-transmission with functional ramifications. There is indication of the later being more possible. The neurotransmitter subpopulation vesicles may be biochemically analysed after the homogenised tissue has undergone subcellular fractionation, apart from the cross contamination likelihood of the vesicle subpopulations, which allows easy criticism of this technique. These experiments have resulted in some clear pattern where the peptide neurotransmitters have their storage in big vesicles that are dense-cored, with non-peptides like the noradrenaline, purine adenosine 5’-triphosphate, acetylcholine and 5-HT existing with the peptide in the small vesicles and to some extent the large vesicles. The response flexibility of the effector tissue could be enhanced by the presence of many transmitters, postjunctionally, since it is certain that various distinct transmitters may simultaneously relay various distinct messages to effector tissues. More common is the pattern where various substances work synergistically in enhancing actions of the others. Co-released substances can also work on both different target cells as well as same target cells in tissues. For instance the double action of the vasoactive intestinal peptide and the acetylcholine in the salivary glands forms vasolidation and also produces stimulation of the secretory cells. This indicated co-transmitter’s functional synergism in the parasympathetic nerves (Lundberg, 1981). Because every transmitter may activate a distinct effector pathway in the cell, the tachyphylaxis or desensitisation, which may have occurred if one pathway was involved, gets avoided as a co-transmission consequence. For instance the vascular smooth muscle contractions might be formed by Ca2+ released by the transmitter from the intracellular store which provides stimulation to the production of the inositol triphosphate, or even by the influx of the Ca2+ through the openings of the ion channels, which have opened due to the activation of the receptor by various transmitters (Spitzer, 2004). . Co-transmitter postjunctional act has been deeply investigated, for instance the noradrenaline and Purine adenosine 5’- triphosphate that is released from sympathetic nerves and which also innervates the vas deferens of the rodents. Vas deferens of rodents as differentiating model for the transmitter postjunctional actions In the vas deferens of rats, smooth muscle’s biphasic contraction is formed by a single sympathetic nerves’ stimulus. The Purine adenosine 5’- triphosphate mediates the first peak while noradrenaline mediates the second. Pharmacological investigations, with the use of selective antagonists, have presented thorough arguments supporting this interpretation (starke, 1991). Agents inhibiting the Purine adenosine 5’- triphosphate actions on the P2 purinoceptors, like Suramin, selectively reduce the initial phase responses. I-adrenoceptor antagonist selectively reduces the second phase. In the vas deferens of the rabbits and the guinea pigs, single sympathetic nerve stimulus results in a mechanical response which is very little or which may fail to happen completely, hence pulse trains that range from 2-32 hertz and which are used for a duration of 10-30 seconds are applied in the investigation of the neurogenic responses. In rats, there is biphasmic response to the pulse trains, with the initial peak starting within 3-4 seconds, later subsiding before the occurrence of the second phase which reaches the peak within 10 seconds. Substantial evidence has also been provided by the antagonist studies which suggest that the sympathetic response’s initial phasic component gets mediated by the Purine adenosine 5’- triphosphate while the second component gets mediated by noradrenaline. Initial pharmacological evidence of co-transmission by Purine adenosine 5’- triphosphate was found by studies that used photoaffinity label arylazidoaminopropionyl- ATP (ANAPP3) which was proven to be inhibiting the sympathetic contraction’s initial phase in both the vas deferens and the contractions to the exogenous Purine adenosine 5’- triphosphate. However, this didn’t affect the neurogenic response’s second phase or the contractions from noradrenaline or even other agonists. The confirmation of the results was through applying the table of ATP analogue, methylene –ATP in the production of the selective desensitisation of the P2 purinoceptors within the tissue (Burnstock, 2006). Mechanical response components are all stopped by the guanethidine and also the 6-hydroxydopamine which cause selective destruction of the noradrenergic nerves, therefore showing that there is no releasing of the Purine adenosine 5’- triphosphate from the purinergic nerves’ distinct population. Reserpine, depleting noradrenaline in noradrenergic nerves, inhibits the response’s second component and not the beginning phasic contraction. A significant characteristic that is relevant to the vas deferens functioning is the consideration that the cells of the smooth muscles in various tissue regions tend to possess some noradrenaline and Purine adenosine 5’- triphosphate sensitivities. There have also been recent indications that vas deferens segments extracted from a rat’s, guinea pig’s or rabbit’s prostatic vas deferens region are almost ten times very sensitive compared to the epididymal segments to the exogenous Purine adenosine 5’- triphosphate, with the epididymal region’s segments ten times more sensitive in comparison to the prostatic segments to the application of the agonists of the exogenous adrenoceptor like the noradrenalin (sneddon, 1992). This therefore creates an implication that even with the releasing of the noradrenaline as well as Purine adenosine 5’- triphosphate in constant quantities throughout the pulse train, contributions to neurogenic responses from the purinergic as well as the noradrenergic considerably varies from one organ region to the next. Vas deferens has the physiological role of propelling the sperm to the urethra right from the epididymal. For the sperm to be directed to the urethra there is dependence on the epididymal end’s contraction that is both slow as well as maintained. This happens when there is a quick expulsion which is formed by prostatic end’s phasic contraction (Nakanishi & Takeda, 1972). Electrophysiological evidence for vas deferens co-transmission Purine adenosine 5’- triphosphate as well as noradrenaline tend to activate transuction mechanisms that are separate to form contractions in the vas deferens. There is also muscle depolarisation, appearing as excitatory junction potential (EJP), when Purine adenosine 5’- triphosphate activates P2 purinoceptors. The EJPS trains summate hence forming action potentials producing Ca2+ through the channels that are voltage-sensitive hence resulting in initial quick contraction. Noradrenaline has very little contribution in the polarisation of the membrane; the stimulation of the adrenoceptor tends to mediate neurogenic contraction’s slow phase through second messenger generation which releases Ca2+ which is stored in sarcoplasmic reticulum (Spitzer, 2004). During the EJPs’ first discovery in the vas deferens around 1960s, there was an assumption that the noradrenaline, the discovered sympathetic nerves’ transmitter, mediated them. It was after two decades that the Purine adenosine 5’- triphosphate selective antagonists were available, which also helped in further proving that EJPs in the vas deferens of the guinea pigs were close to being stopped by the antagonist of P2 purinoceptor (ANAPPP3) although they never had reduction by selected low concentrations of the adrenoceptor antagonist ( Sneddon,1984 ). It was again identified in reserpinised animals where neuronal adrenaline was almost completely depleted while there was continuation of the ATP release, that EJPs had not been reduced as seen under the conditions of control. If compared, the cocaine’s unexpected action (increasing the concentration of the synaptic noradrenaline through re-uptake to avoid its inactivation) was for the depression of the EJPs magnitude. There are also other electrophysiological studies that have used the P2 purinoceptor desensitisation by alpha, beta-methylene ATP (αβ-m AT). The P2 purinoceptor antagonist Suramin (Sneddon, 1992) has also backed up the proposal on ATP mediation of the EJPs. The vas deferens’ P2 purinoceptors are currently considered as P2x in comparison with P2y purinoceptors, which frequently mediates the hyperpolarisation as well as the relaxation of the smooth muscles. The vas deferens’ sympathetic nerves release the NPY acting postjunctionally in enhancing other co-transmitter actions as well as on the transmitters of the NPY2 receptors prejunctionally, thereby mediating a mechanism with negative feedback or the modulation of the neurotransmitter release (Varoqui, 2002). Artery co-transmission A variety of arteries’ sympathetic neurotransmissions tend to include ATP, noradrenaline as well as a variety of peptides together with NPY. When arteries are considered, the muscle’s electrical response to co-transmitters is very complicated compared to the vas deferens’ response. Every sympathetic nerve stimulus forms a quick EJP same in magnitude, pharmacological profile and time course to the vas deferens’. But when arteries are considered, pulse trains form slow depolarization with noradrenaline as the mediator. Noradrenaline and ATP contributions to the sympathetic vasoconstrictions greatly vary in every artery (Starke, 1991). For instance, in the pulmonary artery of rabbits as well as the artery in the tail of rats, the ATP tends to have a very insignificant effect to the sympathetic vasoconstriction. In the mesenteric arteries of both dogs and rats as well as ileocolonic arteries of the rabbit, the biphasic response always has both noradrenergic as well as purinergic phases analogous to vas deferentia, while the small jejunal and saphenous arteries of the rabbit have vasoconstriction majorly through ATP mediation (Pernow, 1992). Apart from noradrenaline and ATP release, there is also the release of the NPY by the particular blood vessels’ or vas deferens’ sympathetic nerves. Currently there is no clarity on the functional role of NPY in the process of neurotransmission. The NPY also acts as a potent vasoconstrictor in some particular arteries, but in consideration of the released low concentrations, potentiating of noradrenaline’s constrictor effect is the action it has predominantly. It may also inhibit the releasing of noradrenaline by prejunctional action. Vas deferens’ electrophysiological investigations have indicated that the reduction of EJPs magnitude can be done by NPY through prejunctionally inhibiting the releasing of ATP. Absence of NPY’s selective antagonist creates difficulty in confirmation of its function in the sympathetic vasoconstrictions. It has also currently been discovered that some arteries of human beings that the release of vasoactive peptides is from sympathetic nerves (NPY with the noradrenaline), parasympathetic nerves (VIP with the histidine isoleucine as well as acetylcholine) as well as sensory nerves (CGRP with the tachykinins). These peptides seem to work like co-transmitters in both sympathetic as well as parasympathetic nerves mainly at stimulation frequencies that are very high with the stimulation in low frequencies releasing them from the sensory nerves (Lundberg, 1991). Bibliography Sneddon, P. & Machalay, M., 1992. Regional variations in purinergic and noradrenergic responses in isolated vas deferens of rat, rabbit and guinea-pig. Journal of Autonomic Pharmacology, 12:421-428. Burnstock, G., 1972.Purinergic nerves. Pharmacological reviews, 24:509-581. Kupferman , I., 1991.Functional studies of cotransmission. Physiological reviews, 71:683-732. 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Starke, K., 1991.Neucleotides as co-transmitters in vascular neuroeffector transmission .Blood vessels, 28:19-26. Pernow, J., 1992.No effect of D-myo-inositol-1, 2, 6-trisphosphate on vasoactive constriction evoked by neuropeptide Y and non-noradrenergic sympathetic nerve stimulation. European journal of pharmacology, 222:171-174. Lundberg, J.M., (1991).Release of vasoactive peptides from autonomic and sensory nerves. Blood vessels 28:27-34. Silinsky, E.M. and Hubbard, J.I., 1973. Release of ATP from motor nerve terminals. Nature 243, 404–405 Vogt, M., (1969), Obituary. Sir Henry Hallett Dale, O.M., F.R.S., International journal of neuropharmacology 8 (2): 83–4. Whittaker, V.P., 1972, the storage and release of acetylcholine by cholinergic nerve terminals: Recent results with non-mammalian preparations. Biochem. Soc. Symp. 49–68 (1972) Burnstock, G., 2006, Historical review: ATP as a neurotransmitter. Trends Pharmacol. Sci. 27, 166–176. Nakanishi, H. & Takeda, H., 1972, The possibility that adenosine triphosphate is an excitatory transmitter in guinea-pig seminal vesicle. Jpn. J. Pharmacol. 22, 269–270. Varoqui, H., 2002, Identification of the differentiation–associated Na+/PI transporter as a novel vesicular glutamate transporter expressed in a distinct set of glutamatergic synapses. J. Neurosci. 22, 142–155. Spitzer, N.C., 2004, Orchestrating neuronal differentiation: Patterns of Ca2+ spikes specify transmitter choice. Trends Neurosci. 27, 415–421. Read More