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Biomedical subjects

R A Challiss

Publications and source records attributed to R A Challiss.

At least 73 records · Page 4Linked to original sources
PubMed1994

Chronic activation of muscarinic and metabotropic glutamate receptors down-regulates type I inositol 1,4,5-trisphosphate receptor expression in cerebellar granule cells.

The ability of receptors coupled to phosphoinositide turnover to evoke accumulation of inositol 1,4,5-trisphosphate (InsP3) over extended incubation periods, and consequently to affect the level of InsP3 receptor expression, was studied in cultured cerebellar granule cells. The cholinergic agonist carbachol (CCh; 1 mM) evoked a biphasic accumulation of InsP3, a rapid three- to fourfold peak increase over control levels at approximately 10 s, decreasing within 1 min to a long-lasting plateau elevation. Using an antibody against the type I InsP3 receptor, it was demonstrated that > 50% down-regulation of type I InsP3 receptor expression in cerebellar granule cells occurred within 1 h of incubation with 1 mM CCh. Over 24 h, 1 mM CCh caused an approximately 85% decrease in type I InsP3 receptor levels, and significant decreases in immunoreactivity were evident at much lower concentrations of CCh. Direct assessment of total InsP3 receptor expression using a radioligand binding method also detected down-regulation, but to an apparently lesser extent. 1-Aminocyclopentane-1S,3R-dicarboxylic acid (200 microM), an agonist of metabotropic glutamate receptors, evoked a marked decrease in type I InsP3 receptors after 24 h of incubation. These findings demonstrate that a functional consequence of maintained InsP3 production in cerebellar granule cells is the down-regulation of InsP3 receptor expression and that this down-regulation may be a common mechanism of action of phosphoinositide-linked receptors during prolonged stimulation.

Animals↗
PubMed1994

Modulatory effects of NMDA on phosphoinositide responses evoked by the metabotropic glutamate receptor agonist 1S,3R-ACPD in neonatal rat cerebral cortex.

1. The effect of NMDA-receptor stimulation on phosphoinositide signalling in response to the metabotropic glutamate receptor agonist 1-aminocyclopentane-1S,3R-dicarboxylic acid (1S,3R-ACPD) has been examined in neonatal rat cerebral cortex slices. 2. Total [3H]-inositol phosphate ([3H]-InsPx) accumulation, in the presence of 5 mM LiCl, in [3H]-inositol pre-labelled slices was concentration-dependently increased by 1S,3R-ACPD (EC50 16.6 microM) and, at a maximally effective concentration, 1S,3R-ACPD (300 microM) increased [3H]-InsPx accumulation by 12.8 fold over basal values. 3. [3H]-InsPx accumulation stimulated by 1S,1R-ACPD was enhanced by low concentrations of NMDA (3-30 microM), but not by higher concentrations (> 30 microM). [3H]-InsPx accumulations stimulated by 1S,3R-ACPD in the absence or presence of 10 microM NMDA were linear with time, at least over the 15 min period examined; however, in the presence of 100 microM NMDA the initial enhancement of 1S,3R-ACPD-stimulated phosphoinositide hydrolysis progressively decreased with time. 4. In the presence of a maximal enhancing concentration of NMDA (10 microM), the response to 1S,3R-ACPD (300 microM) was increased 1.9 fold and the EC50 for agonist-stimulated [3H]-InsPx accumulation decreased about 4 fold. The enhanced response to the metabotropic agonist was concentration-dependently inhibited by competitive and uncompetitive antagonists of NMDA-receptor activation. 5. 1S,3R-ACPD also stimulated inositol 1,4,5-trisphosphate (Ins(1,4,5)P3) mass accumulation with an initial peak response (5-6 fold over basal) at 15 s decaying to a smaller (2 fold), but persistent elevated accumulation (1-10 min). 6. Co-addition of 10 or 100 MicroM NMDA enhanced the initial peak Ins(1,4,5)P3 response to 1S,3RACPD.However, the enhancing effect was only maintained over 10 min in the presence of 1O Micro MNMDA, whilst in contrast, 100 MicroM NMDA ceased to cause a significant enhancement of the metabotropic response by 5 min and completely suppressed lS,3R-ACPD-stimulated Ins(1,4,5)P3 accumulation at 10 min.7. Both basal and 1S,3R-ACPD-stimulated Ins(1,4,5)P3 accumulations were reduced when slices were incubated in nominally Ca2"-free medium. Under these conditions only a concentration-dependent enhancement of the response was observed (EC50 for NMDA facilitation of lS,3R-ACPD-stimulated Ins(1,4,5)P3 accumulation of 32 MicroM).8. These experiments have revealed that at low concentrations, NMDA can dramatically potentiate1S,3R-ACPD-stimulated phosphoinositide hydrolysis, probably by a Ca2"-dependent facilitation of agonist-stimulated phosphoinositide-specific phospholipase C activity. Higher concentrations of NMDA result in time-dependent inhibition of the metabotropic agonist-stimulated response. We believe the former effect could be fundamental in glutamate receptor 'cross-talk', whereas the latter may reflect a Ca2+-dependent neurotoxic effect of NMDA on the neonatal cerebral cortex slices.

2-Amino-5-phosphonovalerate↗
PubMed1994

Phosphoinositide-derived second messengers and the regulation of Ca2+ in vascular smooth muscle.

UNLABELLED: VASCULAR SMOOTH MUSCLE AND THE PHOSPHOINOSITIDE SIGNALLING PATHWAY: Vascular smooth muscle tone can be regulated by an array of agonists which act via receptor-mediated transmembrane signalling pathways to modify the concentrations of key intracellular second messengers. Following agonist stimulation the phosphoinositide signalling pathway initiates the contraction process in vascular smooth muscle, via the second messengers myo-inositol 1,4,5-trisphosphate and sn-1,2-diacylglycerol. DIVERSITY OF CALCIUM-REGULATORY MECHANISMS: The vascular smooth muscle cell apparently sustains the contraction with a number of diverse mechanisms, which act to increase intracellular Ca2+ by regulating both Ca2+ influx across the plasma membrane and Ca2+ release from intracellular calcium stores, or may act in the apparent absence of elevated cytosolic Ca2+ concentrations. FUTURE RESEARCH: The exact nature of these physiological interactions and their exact function are not yet fully understood. In particular, identification of the natural role of specific phospholipase C delta, phospholipase C gamma and protein kinase C isozymes and also the various ryanodine and myo-inositol 1,4,5-trisphosphate receptor subtypes present in vascular smooth muscle will prove critical to future understanding of the regulation of vascular smooth muscle tone in both the normal and the hypertensive phenotype.

Animals↗
PubMed1994

Disruption by lithium of phosphatidylinositol-4,5-bisphosphate supply and inositol-1,4,5-trisphosphate generation in Chinese hamster ovary cells expressing human recombinant m1 muscarinic receptors.

Inhibitory effects of the anti-manic agent lithium on carbachol-stimulated phosphoinositide signaling have been investigated in Chinese hamster ovary (CHO) cells transfected with human m1 muscarinic receptor cDNA (Bmax, 816 fmol/mg of protein). In the presence of Li+, a time-dependent inhibition of inositol-1,4,5-trisphosphate [Ins(1,4,5)P3] mass accumulation was observed within 10 min of agonist addition (IC50 for lithium inhibition at 20 min after carbachol addition, 0.5 mM). The Li(+)-induced decrease in agonist-stimulated Ins(1,4,5)P3 levels was preceded by a dramatic increase in CMP-phosphatidate accumulation. The idea that Li+ blockade of inositol monophosphatase caused a rapid depletion of the cellular myo-inositol pool in CHO-m1 cells was supported by the reversal of Li+ effects by exogenous myo-inositol. Carbachol (1 mM) alone caused a rapid and dramatic decrease in phosphatidylinositol-4,5-bisphosphate [PtdIns(4,5)-P2]in CHO-m1 cells labeled to equilibrium with [3H]-inositol. Carbachol-evoked decreases in PtdIns(4,5)P2 were time-dependently accentuated by Li+ (IC50 for Li+ inhibition at 20 min after carbachol addition, 1.2 mM). Measurements of changes in PtdIns(4,5)P2 mass demonstrated that the effect of Li+ was completely and concentration-dependently reversed by addition of myo-inositol. Sequential 30-min periods of carbachol stimulation resulted in similar time courses of Ins(1,4,5)P3 accumulation when an intervening 20-min recovery period was included in the protocol. Inclusion of Li+ throughout resulted in a more rapid and dramatic attenuation of Ins(1,4,5)P3 during the agonist rechallenge period, which could be correlated with accentuated changes in PtdIns(4,5)P2. These data demonstrate that, although mechanisms operate to efficiently resynthesize PtdIns(4,5)P2, the temporal correlation of carbachol-evoked decreases in PtdIns(4,5)P2 levels in the presence of Li+ strongly suggests that phosphoinositide-specific phospholipase C substrate depletion may be causal in the subsequent decrease in Ins(1,4,5)P3 levels.

Animals↗
PubMed1993

Stereoselectivity of Ins(1,3,4,5)P4 recognition sites: implications for the mechanism of the Ins(1,3,4,5)P4-induced Ca2+ mobilization.

Ins(1,3,4,5)P4 was able to mobilize the entire Ins(1,4,5)P3-sensitive intracellular Ca2+ store in saponin-permeabilized SH-SY5Y human neuroblastoma cells in a concentration-dependent manner, yielding an EC50 value of 2.05 +/- 0.45 microM, compared with 0.14 +/- 0.03 microM for Ins(1,4,5)P3. However, L-Ins(1,3,4,5)P4 [= D-Ins(1,3,5,6)P4] failed to cause mobilization of intracellular Ca2+ at concentrations up to 100 microM. Binding studies using pig cerebellar membranes as a source of both Ins(1,4,5)P3/Ins(1,3,4,5)P4-specific binding sites have revealed a marked contrast in their stereospecificity requirements. Ins(1,4,5)P3-receptors from pig cerebella exhibited stringent stereospecificity, L-Ins(1,4,5)P3 and L-Ins(1,3,4,5)P4 were > 1000-fold weaker, whereas Ins(1,3,4,5)P4 (IC50 762 +/- 15 nM) was only about 40-fold weaker than D-Ins(1,4,5)P3 (IC50 20.7 +/- 9.7 nM) at displacing specific [3H]Ins(1,4,5)P3 binding from an apparently homogeneous Ins(1,4,5)P3 receptor population. In contrast, the Ins(1,3,4,5)P4-binding site exhibited poor stereoselectivity. Ins(1,3,4,5)P4 produced a biphasic displacement of specific [32P]Ins(1,3,4,5)P4 binding, with two-site analysis revealing KD values for high- and low-affinity sites of 2.1 +/- 0.5 nM and 918 +/- 161 nM respectively. L-Ins(1,3,4,5)P4 also produced a biphasic displacement of specific [32P]Ins(1,3,4,5)P4 binding which was less than 10-fold weaker than with D-Ins(1,3,4,5)P4 (IC50 values for the high- and low-affinity sites of 17.2 +/- 3.7 nM and 3010 +/- 542 nM respectively). Therefore, although L-Ins(1,3,4,5)P4 appears to be a high-affinity Ins(1,3,4,5)P4-binding-site ligand in pig cerebellum, it is a very weak agonist at the Ca(2+)-mobilizing receptors of permeabilized SH-SY5Y cells. We suggest that the ability of D-Ins(1,3,4,5)P4 to access intracellular Ca2+ stores may derive from specific interaction with the Ins(1,4,5)P3- and not the Ins(1,3,4,5)P4-receptor population.

Animals↗
PubMed1993

Phospholipase D activation regulates endothelin-1 stimulation of phosphoinositide-specific phospholipase C in SK-N-MC cells.

Endothelin-1 (ET-1) is known to stimulate phospholipase C (PLC) activity in SK-N-MC human neuroblastoma/epithelioma cells: here we show that phospholipase D (PLD) is also stimulated. The generation of inositol 1,4,5-trisphosphate (Ins(1,4,5)P3) by ET-1-stimulated PLC was attenuated by protein kinase C (PKC) activation and enhanced by PKC inhibition. An enhancement of ET-1-stimulated Ins(1,4,5)P3 accumulation was also seen when the product of PLD activity was either diverted into phosphatidyl butanol in the presence of butanol, or phosphatidate phosphohydrolase (PPH) activity was inhibited by DL-propranolol. We conclude that there is an inhibitory, PKC-mediated, feedback loop in these cells which is dependent, in part, on the activation of PKC by product(s) of the PLD/PPH pathway. This provides a novel role for agonist-stimulated PLD activation.

Butanols↗
PubMed1993

Comparison of the effect of isobutylmethylxanthine and phosphodiesterase-selective inhibitors on cAMP levels in SH-SY5Y neuroblastoma cells.

A comparison of the effects of various phosphodiesterase (PDE) inhibitors upon cellular cAMP levels was undertaken in human neuroblastoma SH-SY5Y cells. When inhibitors such as rolipram and Ro 20 1724 (selective for the low Km cAMP-specific PDE) were used, cAMP levels were seen to rise dramatically under basal (< or = 60 fold) or forskolin-stimulated (< or = 200 fold) conditions. However, the non-selective PDE inhibitor isobutylmethylxanthine (IBMX) was 7-18% as effective as these other agents even at 1 mM. The poor efficacy of IBMX was not attributable to concomitant increases in cGMP, to alterations in cAMP egress or to a lack of sensitivity of the cellular PDEs to IBMX inhibition. In additivity experiments, IBMX potently and rapidly reduced cAMP that had accumulated after rolipram treatment. The fact that the agonist 2-chloroadenosine can enhance cAMP accumulation in these cells, and that cAMP elevated by rolipram or forskolin can be reduced by adenosine deaminase and theophylline suggest that cell-derived adenosine enhances cAMP in these cells in an autocrine fashion. Since IBMX is an adenosine receptor antagonist, it is suggested that its blockade of endogenous adenosine effects is at least partly responsible for its poor response when compared to other PDE inhibitors which are weaker adenosine receptor antagonists. These results forewarn against assuming that similar levels of cAMP accumulate after application of PDE inhibitors in these cells.

1-Methyl-3-isobutylxanthine↗
PubMed1993

Exercise-induced improvement in the sensitivity of the rat soleus muscle to insulin is reversed by chloroadenosine--the adenosine receptor agonist.

The effect of 2-chloroadenosine on the sensitivity of the soleus muscle to insulin was measured after rats had been subjected to a single bout of exercise for 1 h at 20 m x min-1. An increased sensitivity of glycolysis to insulin measured in vitro by both lactate production and glucose transport was observed following the acute exercise. This process was reversed by the addition of 2-chloroadenosine, an adenosine receptor agonist, to the incubation medium. This agent had no effect on the exercise-induced increase in the sensitivity of glycogen synthesis to insulin in the same muscle preparation. Our findings confirm earlier studies suggesting that improved insulin sensitivity of glucose utilization by skeletal muscles after endurance exercise may be at least partly explained by an alteration in the adenosine concentration or changes in the properties of adenosine receptors in soleus muscle.

2-Chloroadenosine↗
PubMed1993

Involvement of intracellular stores in the Ca2+ responses to N-Methyl-D-aspartate and depolarization in cerebellar granule cells.

The [Ca2+]i of cerebellar granule cells can be increased in a biphasic manner by addition of NMDA or by depolarization (induced by elevating the extracellular K+ level), which both activate Ca2+ influx. The possibility that these stimuli activate Ca2(+)-induced Ca2+ release was investigated using granule cells loaded with fura 2-AM. Dantrolene, perfused onto groups of cells during the sustained plateau phase of the [Ca2+]i response to K+ or NMDA, was found to reduce the response to both agents in a concentration-dependent manner. Preincubation with thapsigargin (10 microM) substantially reduced the plateau phase of the [Ca2+]i response to K+ and both the peak and plateau phases of the NMDA response. Preincubation with ryanodine (10 microM) also reduced both the K(+)-evoked plateau response and both phases of the NMDA response. Neither had a consistent effect on the peak response to K+. The effects of thapsigargin and ryanodine on the NMDA response were partially additive. These results demonstrate that in cerebellar granule cells a major component of both K(+)- and NMDA-induced elevation of [Ca2+]i appears to be due to release from intracellular stores. The partial additivity of the effects of thapsigargin and ryanodine suggests that these agents affect two overlapping but nonidentical Ca2+ pools.

Animals↗
PubMed1993

Comparative effects of lithium on the phosphoinositide cycle in rat cerebral cortex, hippocampus, and striatum.

The effects of lithium on muscarinic cholinoceptor-stimulated phosphoinositide turnover have been investigated in rat hippocampal, striatal, and cerebral cortical slices using [3H]inositol or [3H]cytidine prelabelling and inositol 1,4,5-trisphosphate [Ins(1,4,5)P3] and inositol 1,3,4,5-tetrakisphosphate [Ins(1,3,4,5)P4] mass determination methods. Carbachol addition resulted in maintained increases in Ins(1,4,5)P3 and Ins(1,3,4,5)P4 mass levels in hippocampus and cerebral cortex, whereas in striatal slices these responses declined significantly over a 30-min incubation period. Carbachol-stimulated Ins(1,4,5)P3 and Ins(1,3,4,5)P4 accumulations were inhibited by lithium in all brain regions studied in a time- and concentration-dependent manner. For example, in hippocampal slices significant inhibitory effects of LiCl were observed at times > 10 min after agonist challenge; IC50 values for inhibition of agonist-stimulated Ins(1,4,5)P3 and Ins(1,3,4,5)P4 accumulations by lithium were 0.22 +/- 0.09 and 0.33 +/- 0.13 mM, respectively. [3H]CMP-phosphatidate accumulation increased in all brain regions when slices were stimulated by agonist and lithium. The ability of myo-inositol to reverse these effects, as well as lithium-suppressed Ins(1,4,5)P3 accumulation, implicates myo-inositol depletion in the action of lithium in the hippocampus and cortex at least. The results of this study suggest that although significant differences in the magnitude and time courses of changes in inositol (poly)phosphate metabolites occur in different brain regions, lithium evokes qualitatively similar enhancements of [3H]inositol monophosphate and [3H]-CMP-phosphatidate levels and inhibitions of Ins(1,4,5)P3 and Ins(1,3,4,5)P4 accumulations. However, the inability of striatal slices to sustain carbachol-stimulated inositol polyphosphate accumulation in the absence of lithium and the inability to reverse effects with myo-inositol may indicate differences in phosphoinositide signalling in this brain region.

Animals↗
PubMed1993

Effects of saturated and polyunsaturated fat enriched diet on the skeletal muscle insulin sensitivity in young rats.

The purpose of this study was to evaluate the effect of diets enriched with fat containing different amounts (30% or 60% total energy) of either saturated (SF) or polyunsaturated fatty acids (PUFA) on glucose tolerance in vivo and insulin sensitivity of glucose utilisation by the soleus muscle in vitro. Young rats were maintained for 28 days after weanling on diets containing either sunflower oil (PUFA), animal fat (butter+lard - SF) or the standard laboratory chow (controls). The sunflower oil added to a diet in moderate quantities (30% total energy) improved the total glucose tolerance, while the diets containing high percentage of PUFA (60%) and moderate or high contents of SF caused impairment of glucose tolerance. The diet with 30% of total energy derived from sunflower oil increased the in vitro sensitivity of glucose utilisation to insulin by the soleus muscle, while in contrast, higher proportions of energy given in a form of PUFA as well as the diets enriched with animal fat impaired the sensitivity of this process to insulin. It is also important to note that the synthesis of glycogen in muscles taken from the rats fed high percentage of saturated fatty acid was found unresponsible to insulin. It is concluded that composition of dietary fat has a profound effect on carbohydrate tolerance and the response of muscle glucose metabolism to insulin. It seems likely that this effect may be at least partly mediated by changes in locally produced prostaglandins.

Animals↗
PubMed1993

Inositol-1,3,4,5-tetrakisphosphate induces calcium mobilization via the inositol-1,4,5-trisphosphate receptor in SH-SY5Y neuroblastoma cells.

myo-Inositol-1,3,4,5-tetrakisphosphate [Ins(1,3,4,5)P4]-induced Ca2+ mobilization was examined in saponin-permeabilized SH-SY5Y cells using myo-inositol hexakisphosphate-supplemented buffer to prevent Ins(1,3,4,5)P4-3-phosphatase-catalyzed back-conversion of exogenous Ins(1,3,4,5)P4 to myo-inositol-1,4,5-trisphosphate [Ins(1,4,5)P3]. The Ins(1,3,4,5)P4 concentration-response curve for Ca2+ release in SH-SY5Y cells exhibited an EC50 of 2.5 microM, compared with 52 nM for Ins(1,4,5)P3, with the maximally effective concentration of Ins(1,3,4,5)P4 (100 microM) mobilizing the entire Ins(1,4,5)P3-sensitive pool. Both Ins(1,3,4,5)P4- and Ins(1,4,5)P3-induced Ca2+ mobilizations were heparin sensitive. Further, L-chiro-inositol-2,3,5-trisphosphorothioate, a recently identified low intrinsic activity Ins(1,4,5)P3 receptor partial agonist, shifted both the Ins(1,4,5)P3 and Ins(1,3,4,5)P4 concentration-response curves significantly rightward, with similar potencies. However, binding studies demonstrate that L-chiro-inositol-2,3,5-trisphosphorothioate interacts very poorly (IC50 > 30 microM) with specific Ins(1,3,4,5)P4 binding sites that have been previously characterized in pig cerebellum. Carbachol-pretreated SH-SY5Y cells (1 mM, > or 6 hr) exhibit a decrease in Ins(1,4,5)P3 receptor number, accompanied by both a rightward shift and a reduced maximal Ca2+ release in their Ins(1,4,5)P3 concentration-response curve. Here both Ins(1,4,5)P3 and Ins(1,3,4,5)P4 concentration-response curves were found to exhibit identically reduced maximal Ca2+ release responses and about 4-fold rightward shifts in EC50 values. Together, these observations provide compelling evidence for our hypothesis that Ins(1,3,4,5)P4 exhibits weak but full agonist status at Ins(1,4,5)P3 receptor-operated Ca2+ channels in SH-SY5Y cells.

Calcium↗
PubMed1992

Evidence for lithium-sensitive inositol 4,5-bisphosphate accumulation in muscarinic cholinoceptor-stimulated cerebral-cortex slices.

Stimulation of [3H]inositol-prelabelled rat cerebral-cortex slices with carbachol results in the accumulation of four [3H]inositol bisphosphate isomeric species, Ins(1,3)P2, Ins(1,4)P2, Ins(3,4)P2 and Ins(4,5)P2. Although the last isomer ran as a minor peak on h.p.l.c., its accumulation was dramatically enhanced in the presence of Li+ (1 mM), such that at 30 min it represented almost 35% of the total bisphosphate fraction. The accumulation of Ins(4,5)P2 appeared to be very sensitive to Li+ (EC50 = 94 +/- 3 microM), strongly implicating a Li(+)-sensitive metabolism. Evidence for this is provided from the rapid but Li(+)-sensitive decay of Ins(4,5)P2 when muscarinic-receptor stimulation is antagonized by atropine at a time when accumulations have reached a new steady state. Manipulation of phospholipase D by activators and inhibitors of protein kinase C did not suggest a role for phospholipase D hydrolysis of PtdInsP2 in the formation of Ins(4,5)P2. Attempts to reveal Ins(4,5)P2 metabolism, or indeed its synthesis from Ins(1,4,5)P3, were not successful with broken cell preparations and strongly suggest discrete compartmentation of inositol phosphate metabolism in the intact cell.

Animals↗
PubMed1992

Characterization of the adenosine receptor modulating insulin action in rat skeletal muscle.

The pharmacological profile of adenosine receptors in rat soleus muscle has been investigated by studying the effects of A1-and A2-selective adenosine receptor agonists on glucose utilization and the system A amino acid transporter under conditions where adenosine has been reported to exert a modulatory action on these insulin-sensitive processes. In the presence of adenosine deaminase and a sub-maximally effective concentration of insulin (50 microU/ml), the A1-selective agonists N6-cyclopentyladenosine and R(-)-N6-(2-phenylisopropyl)adenosine (R(-)PIA) caused concentration-dependent inhibitions of 2-deoxy[3H]glucose 6-phosphate and alpha-[14C]methylaminoisobutyric acid accumulations, but had no effect on the rate of [14C]glucose incorporation into glycogen, in incubated soleus muscle strips. These effects on glucose transport/phosphorylation and system A amino acid transport could be antagonized by 8-cyclopentyl-1,3- dipropylxanthine and 8-phenyltheophylline. The A2-selective adenosine receptor agonists CGS 21680 and 2-(phenylamino)adenosine were much less potent in their inhibition of these metabolic processes. These data support the proposal that adenosine exerts a post-receptor insulin-modulatory action in skeletal muscle and strongly suggest that this action is mediated by A1 adenosine receptors: the possible intracellular signalling mechanism(s) for this hormone-modulatory effect of adenosine are discussed.

Adenosine Deaminase↗