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Biomedical subjects

R T Miller

Publications and source records attributed to R T Miller.

At least 37 records · Page 2Linked to original sources
PubMed1999

Platelets from thrombocytopenic ponies acutely infected with equine infectious anemia virus are activated in vivo and hypofunctional.

Thrombocytopenia is a consistent finding and one of the earliest hematological abnormalities in horses acutely infected with equine infectious anemia virus (EIAV), a lentivirus closely related to human immunodeficiency virus. Multifactorial mechanisms, including immune-mediated platelet destruction and impaired platelet production, are implicated in the pathogenesis of EIAV-associated thrombocytopenia. This study was undertaken to investigate whether regenerative thrombopoiesis and platelet destruction occurred in ponies acutely infected with EIAV. Circulating large, immature platelets were increased in ponies acutely infected with EIAV late in the infection when platelet count was at a nadir. Morphometric analysis of bone marrow from acutely infected ponies revealed significant increased in megakaryocyte area and megakaryocyte nuclear area. A trend toward increased numbers of megakaryocytes was also observed. Platelets from acutely infected ponies had increased surface-bound fibrinogen and ultrastructural changes consistent with in vivo platelet activation. Platelets also had hypofunctional aggregation responses to three agonists in vitro. We conclude that thrombocytopenia in ponies acutely infected with EIAV is regenerative and suggest that bone marrow platelet production is not severely compromised in these ponies. Our findings reveal that in vivo platelet activation occurs in ponies acutely infected with EIAV, and as a result platelets are hypofunctional in vitro. Activation of platelets in vivo may cause platelet degranulation or formation of platelet aggregates, which would result in removal of these damages platelets from circulation. This may represent a form of nonimmune-mediated platelet destruction in ponies acutely infected with EIAV.

Animals↗
PubMed1999

Zinc content of Escherichia coli-expressed constitutive isoforms of nitric-oxide synthase. Enzymatic activity and effect of pterin.

Recently, we obtained x-ray crystallographic data showing the presence of a ZnS4 center in the structure of Escherichia coli-expressed bovine endothelial nitric-oxide synthase (eNOS) and rat neuronal nitric-oxide synthase (nNOS). The zinc atom is coordinated by two CXXXXC motifs, one motif being contributed by each NOS monomer (cysteine 326 through cysteine 331 in rat nNOS). Mutation of the nNOS cysteine 331 to alanine (C331A) results in the loss of NO. synthetic activity and also results in an inability to bind zinc efficiently. Although prolonged incubation of the C331A mutant of nNOS with high concentrations of L-arginine results in a catalytically active enzyme, zinc binding is not restored. In this study, we investigate the zinc stoichiometry in wild-type nNOS and eNOS, as well as in the C331A-mutated nNOS, using a chelation assay and electrothermal vaporization-inductively coupled plasma-mass spectrometry. The data reveal an approximate 2:1 stoichiometry of heme to zinc in (6R)-5,6,7,8-tetrahydro-L-biopterin-replete, wild-type nNOS and eNOS and show that the reactivated C331A mutant of nNOS has a limited ability to bind zinc. The present study substantiates that the zinc in NOS is structural rather than catalytic and is important for maintaining optimally functional, enzymatically active, constitutive NOSs.

Arginine↗
PubMed1999

Alteration of protein kinase C isoform-specific expression during rat hepatocarcinogenesis after exposure to the peroxisome proliferator WY-14,643.

The role of protein kinase C (PKC) isoforms in mediating peroxisome proliferator chemical- (PPC) induced hepatocarcinogenesis was examined. After an acute gavage exposure to WY-14,643 (WY) membrane-bound PKCdelta and cytosolic PKCbeta decreased, whereas the expression of the other isoforms was not altered. After a 13-week chronic exposure, membrane-bound PKCbeta, delta and zeta levels decreased. In WY-induced hepatocellular adenomas, PKCalpha was increased, and PKCbeta was further decreased in membrane fractions. These results, taken together with previous studies, indicate that alterations in PKCalpha, beta and delta isoforms, which regulate mitogenesis, could play important roles in perpetuating the high cell proliferative rate in PPC-induced hepatocellular adenomas.

Adenoma↗
PubMed1999

The stimulatory effects of Hofmeister ions on the activities of neuronal nitric-oxide synthase. Apparent substrate inhibition by l-arginine is overcome in the presence of protein-destabilizing agents.

A variety of monovalent anions and cations were effective in stimulating both calcium ion/calmodulin (Ca2+/CaM)-independent NADPH-cytochrome c reductase activity of, and Ca2+/CaM-dependent nitric oxide (NO.) synthesis by, neuronal nitric oxide synthase (nNOS). The efficacy of the ions in stimulating both activities could be correlated, in general, with their efficacy in precipitating or stabilizing certain proteins, an order referred to as the Hofmeister ion series. In the hemoglobin capture assay, used for measurement of NO. production, apparent substrate inhibition by L-arginine was almost completely reversed by the addition of sodium perchlorate (NaClO4), one of the more effective protein-destabilizing agents tested. Examination of this phenomenon by the assay of L-arginine conversion to L-citrulline revealed that the stimulatory effect of NaClO4 on the reaction was observed only in the presence of oxyhemoglobin or superoxide anion (generated by xanthine and xanthine oxidase), both scavengers of NO. Spectrophotometric examination of nNOS revealed that the addition of NaClO4 and a superoxide-generating system, but neither alone, prevented the increase of heme absorption at 436 nm, which has been attributed to the nitrosyl complex. The data are consistent with the release of autoinhibitory NO. coordinated to the prosthetic group of nNOS, which, in conjunction with an NO. scavenger, causes stimulation of the reaction.

Anions↗
PubMed1999

Rapid kinetic studies of electron transfer in the three isoforms of nitric oxide synthase.

The nitric oxide synthases (NOSs) consist of a flavin-containing reductase domain, linked to a heme-containing oxygenase domain, by a calmodulin (CaM) binding sequence. The flavin-containing reductase domains of the NOS isoforms possess close sequence homology to NADPH-cytochrome P450 reductase (CPR). Additionally, the oxygenase domains catalyze monooxygenation of L-arginine through a cytochrome P450-like cysteine thiolate-liganded heme bound in the active site. With these considerations in mind, we conducted studies in an attempt to gain insight into the intermediates involved in flavoprotein-to-heme electron transfer in the NOSs. Static, steady-state, and stopped-flow kinetic studies indicated that nNOS must be reduced to a more than one-electron-reduced intermediate before efficient electron transfer can occur. Therefore, the possibility exists that the oxygenase domains of the NOS isoforms may receive their electrons from the reductase domains by a mechanism resembling the CPR-P450 interaction. Furthermore, the rate-limiting step in electron transfer appears to be the transfer of electrons from the flavoprotein to the oxygenase domain facilitated by the binding of CaM at increased intracellular Ca(2+) concentrations. Thus, modulation of electron transfer rates appears to be regulated at the level of the flavoprotein domains of the NOS isoforms.

Animals↗
PubMed1999

Assay of isoforms of Escherichia coli-expressed nitric oxide synthase.

The techniques described herein have added to our repertoire of experimental approaches for the characterization of the NOSs. These procedures have reinforced our conviction that the NOSs are structurally suited to perform unique functions in their cellular milieux and that these differences have physiological consequences.

Bacterial Proteins↗
PubMed1999

A comprehensive approach to clustering of expressed human gene sequence: the sequence tag alignment and consensus knowledge base.

The expressed human genome is being sequenced and analyzed by disparate groups producing disparate data. The majority of the identified coding portion is in the form of expressed sequence tags (ESTs). The need to discover exonic representation and expression forms of full-length cDNAs for each human gene is frustrated by the partial and variable quality nature of this data delivery. A highly redundant human EST data set has been processed into integrated and unified expressed transcript indices that consist of hierarchically organized human transcript consensi reflecting gene expression forms and genetic polymorphism within an index class. The expression index and its intermediate outputs include cleaned transcript sequence, expression, and alignment information and a higher fidelity subset, SANIGENE. The STACK_PACK clustering system has been applied to dbEST release 121598 (GenBank version 110). Sixty-four percent of 1,313, 103 Homo sapiens ESTs are condensed into 143,885 tissue level multiple sequence clusters; linking through clone-ID annotations produces 68,701 total assemblies, such that 81% of the original input set is captured in a STACK multiple sequence or linked cluster. Indexing of alignments by substituent EST accession allows browsing of the data structure and its cross-links to UniGene. STACK metaclusters consolidate a greater number of ESTs by a factor of 1. 86 with respect to the corresponding UniGene build. Fidelity comparison with genome reference sequence AC004106 demonstrates consensus expression clusters that reflect significantly lower spurious repeat sequence content and capture alternate splicing within a whole body index cluster and three STACK v.2.3 tissue-level clusters. Statistics of a staggered release whole body index build of STACK v.2.0 are presented.

Algorithms↗
PubMed1999

Endothelin-B receptors activate Galpha13.

Endothelin (ET) receptors activate heterotrimeric G proteins that are members of the Gi, Gq, and Gs families but may also activate members of other families such as Galpha12/13. Galpha13 has multiple complex cellular effects that are similar to those of ET. We studied the ability of ET receptors to activate Galpha13 using an assay for G protein alpha-chain activation that is based on the fact that an activated (GTP-bound) alpha-chain is resistant to trypsinization compared with an inactive (GDP-bound) alpha-chain. Nonhydrolyzable guanine nucleotides and AlMgF protected Galpha13 from degradation by trypsin. In membranes from human embryonic kidney 293 cells that coexpress ETB receptors and alpha13, ET-3 and 5'-guanylylimidodiphosphate [Gpp(NH)p] increased the protection of alpha13 compared with Gpp(NH)p alone. The specificity of ETB receptor-alpha13 coupling was documented by showing that beta2 receptors and isoproterenol or ETA receptors and ET-1 did not activate alpha13 and that a specific antagonist for ETB receptors blocked ET-3-dependent activation of alpha13.

Cell Line↗
PubMed1998

The C331A mutant of neuronal nitric-oxide synthase is defective in arginine binding.

It has been proposed that Cys99 of human endothelial nitric oxide synthase (eNOS) is responsible for tetrahydrobiopterin (BH4) binding. To examine this possibility rigorously, we expressed rat neuronal NOS (nNOS) in Escherichia coli, with the homologous Cys331 to Ala mutation, and characterized structural and functional attributes of the purified, mutated enzyme. C331A-nNOS, as isolated, was catalytically incompetent. Upon prolonged incubation with L-arginine (L-Arg), not only BH4 binding but also catalytic activity could be restored. In contrast to wild-type nNOS (WT-nNOS), which exhibits an absorbance maximum at 407 nm that shifts immediately upon L-arginine addition to a high spin form, the C331A-nNOS mutant, as isolated, exhibited an absorbance maximum at 420 nm. C331A-nNOS, as isolated, did not bind detectable levels of either [3H]Nomega-nitro-L-arginine or [3H]BH4, but [3H]BH4 binding was reinstated after extended incubation with excess L-arginine. On the other hand, C331A-nNOS and WT-NOS were identical with regard to imidazole binding affinity, CaM binding affinity, and rates of cytochrome c and 2, 6-dichlorophenolindophenol reduction. EPR spectroscopy revealed conversion of low to high spin heme after extended incubation with high concentrations of L-arginine (0.1-10 mM). The estimated Kd for L-arginine binding to C331A-nNOS was two orders of magnitude greater than WT-nNOS (>100 microM versus 2-3 microM). Here we propose that Cys331 plays an important role in stabilizing L-arginine binding to nNOS. Our findings suggest that the primary dysfunction in the C331A mutant of nNOS, as isolated, is disruption of the BH4-substrate binding interactions as broadcast from this mutated cysteine residue. Prolonged incubation with L-arginine appears to cause remodeling of the mutant protein to a form similar to that of WT-nNOS, allowing for normalized BH4 binding and nitric oxide synthetic activity.

Animals↗
PubMed1998

Cutaneous lymphoma with extensive periarticular involvement in a horse.

Two months after colic surgery, subcutaneous masses were found on the ventral and lateral portions of the thorax of a 3-year-old Hanoverian-cross filly. Six months later, the filly was admitted for evaluation of severe lameness. Arthrocentesis of the tarsocrural joint yielded clotted sanguineous material; however, unusual multinucleated giant cells were seen. Radiography of the right tarsus revealed soft tissue opacity and degenerative joint disease. The filly was euthanatized to prevent further suffering. At necropsy, multiple soft-tissue masses were located throughout the fascial planes of the tarsi and in the subcutis of the ventral and lateral portions of the thorax. Neoplasms consisted primarily of a large number of mature well-differentiated T lymphocytes. On the basis of these findings, the diagnosis was cutaneous lymphoma with unusual involvement of periarticular tissues. Severe degenerative joint disease in the right tarsus did not appear to be associated with the tumors.

Animals↗
PubMed1998

Conformational changes in a mammalian voltage-dependent potassium channel inactivation peptide.

Fast inactivation is restored in inactivation deletion mutant voltage-gated potassium (Kv) channels by application of synthetic inactivation 'ball' peptide. Using Fourier transform infrared and circular dichroism spectroscopy, we have investigated the structure of synthetic Kv3.4 channel ball peptide, in a range of environments relevant to the function of the ball domain. The ball peptide contains no alpha-helix or beta-sheet in reducing conditions in aqueous solution, but when cosolubilized with anionic lipid or detergent in order to mimic the environment which the ball domain encounters during channel inactivation, the ball peptide adopts a partial beta-sheet structure. Oxidation of the Kv3.4 ball peptide facilitates formation of a disulfide bond between Cys6 and Cys24 and adoption of a partial beta-sheet structure in aqueous solution; the tendency of the oxidized ball peptide to adopt beta-sheet is generally greater than that of the reduced ball peptide in a given environment. THREADER modeling of the Kv3.4 ball peptide structure predicts a beta-hairpin-like conformation which corresponds well to the structure suggested by spectroscopic analysis of the ball peptide in its cyclic arrangement. A V7E mutant Kv3.4 ball peptide analogue of the noninactivating Shaker B L7E mutant ball peptide cannot adopt beta-structure whatever the environment, and regardless of oxidation state. The results suggest that the Kv3.4 ball domain undergoes a conformational change during channel inactivation and may implicate a novel regulatory role for intramolecular disulfide bond formation in the Kv3.4 ball domain in vivo.

Amino Acid Sequence↗
PubMed1998

Urinary loss of immunoglobulin G anti-F(ab)2 and anti-DNA antibody in systemic lupus erythematosus nephritis.

The objective of this study was to determine whether the low levels of serum immunoglobulin G (IgG) anti-F(ab)2 seen in some patients with active systemic lupus erythematosus (SLE) were directly related to the deposition of antibody with this specificity in the kidney or alternatively to the urinary loss of IgG anti-F(ab)2. Serum Levels of IgG anti-F(ab)2, anti-tetanus toxoid, and anti-ds DNA antibody were measured in parallel with urinary excretion of these same 3 antibodies in 28 patients with SLE nephritis and in 28 control patients with other forms of chronic kidney disease. Low levels of both serum IgG anti-F(ab)2 or anti-tetanus antibody appeared to correlate with increased levels of urinary loss of these same antibodies in some patients with SLE and in control subjects with kidney disease. However, urinary loss could not account for low serum levels of either IgG antibody in many subjects. Quantitative 24-hour urinary losses of IgG anti-F(ab)2 and anti-DNA were much higher in patients with SLE than in control subjects with kidney disease (P < .05), whereas amounts of IgG urinary loss of anti-tetanus were similar in patients with SLE and in control subjects. In nearly 1 third of SLE nephritis patients, 13% to 53% of total excreted urinary IgG showed anti-DNA enzyme-linked-immunosorbent assay reactivity. Urinary IgG in many patients with SLE showed both anti-DNA and anti-F(ab)2 reactivity, but dual anti-DNA/F(ab)2 specificity was more pronounced in affinity-isolated serum IgG anti-DNA or anti-F(ab)2 than in excreted urinary IgG molecules. The affinity of urinary IgG for either DNA or F(ab)2 was much lower than the same antibody activities measured either in serum or in kidney biopsy eluates. When the relative affinity of anti-DNA antibody in serum, urine, and kidney biopsy eluate was measured in parallel, the highest affinity antibody was found in kidney biopsy eluates, followed by serum antibody with urine antibody affinity showing the lowest values. These findings suggest a relative concentration of the highest affinity, doubly reactive IgG anti-DNA/F(ab)2 in SLE kidney tissues during SLE nephritis and implicate this process as an important factor in ongoing tissue damage.

Adolescent↗
PubMed1998

Hyperglobulinemia and lymphocyte subset changes in naturally infected, inapparent carriers of equine infectious anemia virus.

OBJECTIVE: To determine blood protein concentration, immunoglobulin concentration, and lymphocyte profiles in equine infectious anemia virus (EIAV) seropositive, naturally infected horses without clinical signs of disease. ANIMALS: 26 clinically normal seropositive horses, 6 febrile ponies with experimentally induced EIA, and 52 clinically normal seronegative horses and ponies. PROCEDURE: Serum and EDTA-anticoagulated blood were obtained from all horses and ponies, and total serum protein and albumin concentrations, immunoglobulin concentrations, and blood lymphocyte subset counts were determined. RESULTS: Compared with seronegative horses, EIAV seropositive inapparent carrier horses had no significant difference in serum reverse transcriptase activity, PCV, or platelet count. Inapparent carrier horses had increased plasma total solids and serum globulin concentrations and decreased serum albumin concentration and albumin-to-globulin ratio. Total serum immunoglobulin and serum IgM concentrations were increased. Inapparent carrier horses had significantly decreased percentages of CD5+ and CD4+ blood lymphocytes. CONCLUSIONS: Serum protein and lymphocyte subset changes in EIAV-infected inapparent carrier horses are consistent with immune activation or chronic inflammation, both of which may, in part, be the result of virus-induced polyclonal B-cell activation. CLINICAL RELEVANCE: EIAV seropositive horses have immune-related abnormalities consistent with ongoing viral activity regardless of the duration they have been infected, even when the usual signs of disease (anemia, fever, weight loss) are not apparent.

Animals↗
PubMed1997

Involvement of the reductase domain of neuronal nitric oxide synthase in superoxide anion production.

Neuronal nitric oxide synthase (nNOS) is a modular enzyme which consists of a flavin-containing reductase domain and a heme-containing oxygenase domain, linked by a stretch of amino acids which contains a calmodulin (CaM) binding site. CaM binding to nNOS facilitates the transfer of NADPH-derived electrons from the reductase domain to the oxygenase domain, resulting in the conversion of L-arginine to L-citrulline with the concomitant formation of a guanylate cyclase activating factor, putatively nitric oxide. Numerous studies have established that peroxynitrite-derived nitrogen oxides are present following nNOS turnover. Since peroxynitrite is formed by the diffusion-limited reaction between the two radical species, nitric oxide and O2.-, we employed the adrenochrome assay to examine whether nNOS was capable of producing O2.- during catalytic turnover in the presence of L-arginine. To differentiate between the role played by the reductase domain and that of the oxygenase domain in O2.- production, we compared its production by nNOS against that of a nNOS mutant (CYS-331), which was unable to transfer NADPH-derived electrons efficiently to the heme iron under special conditions, and against that of a flavoprotein module construct of nNOS. We report that O2.- production by nNOS and the CYS-331 mutant is CaM-dependent and that O2.- production can be modulated by substrates and inhibitors of nNOS. O2.- was also produced by the reductase domain of nNOS; however, it did not display the same CaM dependency. We conclude that both the reductase and oxygenase domains of nNOS produce O2.-, but that the reductase domain is both necessary and sufficient for O2.- production.

Adrenochrome↗
PubMed1997

Secondary structure, stability and tetramerisation of recombinant K(V)1.1 potassium channel cytoplasmic N-terminal fragment.

The recombinant N-terminal fragment (amino acids 14-162) of a tetrameric voltage-gated potassium channel (K(V)1.1) has been studied using spectroscopic techniques. Evidence is presented that it forms a tetramer in aqueous solution, whereas when solubilised in 1% Triton X-100 it remains monomeric. The secondary structure content of both monomeric and tetrameric K(V)1.1 N-terminal fragment has been estimated from FTIR and CD spectroscopy to be 20-25% alpha-helix, 20-25% beta-sheet, 20% turns and 30-40% random coil. Solubilisation of the protein in detergent is shown by hydrogen-deuterium exchange analysis to alter tertiary structure rather than secondary structure and this may be the determining factor in tetramerisation ability. Using molecular modelling we propose a supersecondary structure consisting of two structural domains.

Amino Acid Sequence↗
PubMed1997

2,5-Bis-(glutathion-S-yl)-alpha-methyldopamine, a putative metabolite of (+/-)-3,4-methylenedioxyamphetamine, decreases brain serotonin concentrations.

3,4-(+/-)-Methylenedioxyamphetamine (MDA) and 3,4-(+/-)-methylenedioxymethamphetamine (MDMA) are serotonergic neurotoxicants. However, when injected directly into brain, MDA and MDMA are not neurotoxic, suggesting that systemic metabolism plays an important role in the development of neurotoxicity. The nature of the metabolite(s) responsible for MDA- and MDMA-mediated neurotoxicity is unclear. alpha-Methyldopamine is a major metabolite of MDA and is readily oxidized to the o-quinone, followed by conjugation with glutathione (GSH). Because the conjugation of quinones with GSH frequently results in preservation or enhancement of biological (re)activity, we have been investigating the role of quinone-thioethers in the acute and long-term neurochemical changes observed after administration of MDA. Although intracerebroventricular (i.c.v.) administration of 5-(glutathion-S-yl)-alpha-methyldopamine (4 x 720 nmol) and 5-(N-acetylcystein-S-yl)-alpha-methyldopamine (1 x 7 nmol) to Sprague-Dawley rats produced overt behavioral changes similar to those seen following administration of MDA (93 mumol/kg, s.c.) they did not produce long-term decreases in brain serotonin (5-hydroxytryptamine, 5-HT) concentrations. In contrast, 2,5-bis-(glutathion-S-yl)-alpha-methyldopamine (4 x 475 nmol) decreased 5-HT levels by 24%, 65% and 30% in the striatum, hippocampus and cortex, respectively, 7 days after injection. The relative sensitivity of the striatum, hippocampus and cortex to 2,5-bis-(glutathion-S-yl)-alpha-methyldopamine was the same as that observed for MDA; the absolute effects were greater with MDA. The effects of 2,5-bis-(glutathion-S-yl)-alpha-methyldopamine were also selective for serotonergic nerve terminal fields, in that 5-HT levels were unaffected in regions of the cell bodies. Because 2,5-bis-(glutathion-S-yl)-alpha-methyldopamine caused long-term depletion in 5-HT without adversely affecting the dopaminergic system, it also mimics the selectivity of MDA/MDMA. The data imply a possible role for quinone-thioethers in the neurobehavioral and neurotoxicological effects of MDA/MDMA.

3,4-Methylenedioxyamphetamine↗
PubMed1997

Inhibition of nitric oxide synthase activity and nitric oxide-dependent calcium influx in renal epithelial cells by cyclic adenosine monophosphate: implications for cell injury.

Cell injury frequently occurs in the setting of tissue destruction and inflammation and is associated with a rise in intracellular calcium (Cai) and increased NO production. The mechanisms that trigger rises in Cai and NO during cell injury are not fully defined, but they may involve activation of G protein-coupled receptors for substances such as bradykinin, Ang II, thromboxane, and thrombin. These receptors act through G proteins from different families that have distinct functions. Receptors for bradykinin and Ang II act through members of the G alpha i and G alpha q families, whereas receptors for thrombin and thromboxane act through members of the G alpha i, G alpha q, and G alpha 12/13 families. These G proteins cooperate to regulate Cai and NO in epithelial cells through distinct mechanisms. In a number of experimental settings, activators of the adenylyl cyclase system reduce the severity of cell injury. To understand the mechanisms by which G protein-dependent signaling systems may contribute to cell injury and to define the role of adenylyl cyclase in ameliorating cell injury, the effects of adenylyl cyclase on bradykinin-stimulated Ca influx and NO in cultured renal epithelial cells that stably overexpress G alpha q and G alpha 13 were studied. This system allowed for the separation of different components of the signals initiated by receptors for thromboxane and thrombin. G alpha 13 increased bradykinin-stimulated Ca influx by a mechanism that depends on NO and cGMP. The increased Ca influx was blocked by inhibitors of NO synthase and guanylyl cyclase and by activation of adenylyl cyclase. NO production was inhibited by activators of cAMP-dependent protein kinase, which indicated that cAMP blocks Ca influx by inhibiting NO production. Expression of G alpha q, the G protein that regulates phospholipase C, also increased bradykinin-stimulated Ca influx, but by an NO, cGMP-independent mechanism that was insensitive to inhibition by adenylyl cyclase. The authors conclude that Ca influx is modulated by NO-dependent and independent mechanisms, and that to the extent that increased NO production contributes to increased Ca influx and cell injury, cell injury may be reduced by agents that activate adenylyl cyclase.

Adenylyl Cyclases↗