The Extracellular cAMP-Adenosine Pathway Regulates Expression of Renal D1 Dopamine Receptors in Diabetic Rats

Kuzhikandathil, Eldo V.; Clark, Leslie H.; Li, Ying

doi:10.1074/jbc.m111.268136

Cited by 9 publications

(7 citation statements)

References 44 publications

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“…The extracellular 3=,5=-cAMP-adenosine pathway may also provide a chemical connection by which the liver can affect the kidney (48), and very recent studies by Kuzhikandathil et al (61) support the concept that the extracellular 3=,5=-cAMP-adenosine pathway is also involved in regulating renal D1 dopamine receptor expression.…”

Section: A Brief Digression: the 3=5=-camp-adenosine Pathwaymentioning

confidence: 86%

The 2′,3′-cAMP-adenosine pathway

Jackson

2011

American Journal of Physiology-Renal Physiology

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.-Our recent studies employing HPLC-tandem mass spectrometry to analyze venous perfusate from isolated, perfused kidneys demonstrate that intact kidneys produce and release into the extracellular compartment 2=,3=-cAMP, a positional isomer of the second messenger 3=,5=-cAMP. To our knowledge, this represents the first detection of 2=,3=-cAMP in any cell/tissue/ organ/organism. Nuclear magnetic resonance experiments with isolated RNases and experiments in isolated, perfused kidneys suggest that 2=,3=-cAMP likely arises from RNase-mediated transphosphorylation of mRNA. Both in vitro and in vivo kidney experiments demonstrate that extracellular 2=,3=-cAMP is efficiently metabolized to 2=-AMP and 3=-AMP, both of which can be further metabolized to adenosine. This sequence of reactions is called the 2=,3=-cAMP-adenosine pathway (2=,3=-cAMP ¡ 2=-AMP/3=-AMP ¡ adenosine). Experiments in rat and mouse kidneys show that metabolic poisons increase extracellular levels of 2=,3=-cAMP, 2=-AMP, 3=-AMP, and adenosine; however, little is known regarding the pharmacology of 2=,3=-cAMP, 2=-AMP, and 3=-AMP. What is known is that 2=,3=-cAMP facilitates activation of mitochondrial permeability transition pores, a process that can lead to apoptosis and necrosis, and inhibits proliferation of vascular smooth muscle cells and glomerular mesangial cells. In summary, there is mounting evidence that at least some types of cellular injury, by triggering mRNA degradation, engage the 2=,3=-cAMP-adenosine pathway, and therefore this pathway should be added to the list of biochemical pathways that produce adenosine. Although speculative, it is possible that the 2=,3=-cAMP-adenosine pathway may protect against some forms of acute organ injury, for example acute kidney injury, by both removing an intracellular toxin (2=,3=-cAMP) and increasing an extracellular renoprotectant (adenosine). 2=-AMP; 3=-AMP; kidney Discovery of 2=,3=-cAMP in a Biological SystemLIQUID CHROMATOGRAPHY-TANDEM mass spectrometry (LC-MS/MS) combines the resolving power of HPLC with the detection sensitivity and specificity of tandem mass spectrometry (MS/MS). With MS/MS, a precursor ion is selected for further fragmentation and a product ion is selectively detected and quantified, an analytic procedure known as selected reaction monitoring (SRM). While investigating, using LC-MS/MS in the SRM mode, the release of 3=,5=-cAMP from isolated, perfused rat kidneys, we noted an unexpected chromatographic peak that was not 3=,5=-cAMP (82). Despite the risks of being distracted by "analytic trash," this serendipitous observation was too intriguing to ignore. So, we deviated from our original experimental plan and instead focused on determining the identity of this unknown substance. We knew that the massto-charge ratio (m/z) of the precursor ion for the unknown was the same as the m/z for the precursor ion of 3=,5=-cAMP and that the m/z for the product ion for the unknown was the same as the m/z of the product ion for 3=,5=-cAMP (hence the SRM signal designed to detect only 3=,5=-cA...

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Section: A Brief Digression: the 3=5=-camp-adenosine Pathwaymentioning

confidence: 86%

The 2′,3′-cAMP-adenosine pathway

Jackson

2011

American Journal of Physiology-Renal Physiology

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“…Two examples focus on cyclic adenosine monophosphate (cAMP) as a signal molecule candidate. The extracellular release of cAMP is known to exert effects such as receptor expression in renal cells (Kuzhikandathil et al, 2011) and inhibition of skeletal muscle inotropism (Duarte et al, 2012). Before addressing further questions, such as if hemichannels are involved in a paracrine-like delivery of cAMP, it is essential to understand the characteristics of hemichannel permeability.…”

Section: Introductionmentioning

confidence: 99%

Cyclic nucleotide permeability through unopposed connexin hemichannels

Valiūnas¹

2013

Front. Pharmacol.

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Cyclic adenosine monophosphate (cAMP) is a well-known intracellular and intercellular second messenger. The membrane permeability of such molecules has potential importance for autocrine-like or paracrine-like delivery. Here experiments have been designed to demonstrate whether gap junction hemichannels, composed of connexins, are a possible entrance pathway for cyclic nucleotides into the interior of cells. HeLa cells stably expressing connexin43 (Cx43) and connexin26 (Cx26) were used to study the cyclic nucleotide permeability of gap junction hemichannels. For the detection of cAMP uptake, the cells were transfected using the cyclic nucleotide-modulated channel from sea urchin sperm (SpIH) as the cAMP sensor. SpIH derived currents (Im) were recorded in whole-cell/perforated patch clamp configuration. Perfusion of the cells in an external K+ aspartate- (KAsp) solution containing 500 μM cAMP and no extracellular Ca2+, yielded a five to sevenfold increase in the Im current level. The SpIH current increase was associated with detectable hemichannel current activity. Depolarization of cells in Ca2+-free NaCl perfusate with 500 μM cAMP also induced a SpIH current increase. Elevating extracellular Ca2+ to mM levels inhibited hemichannel activity. Perfusion with a depolarizing KAsp solution containing 500 μM cAMP and 2 mM Ca2+ did not increase SpIH currents. The addition of the gap junction blocker carbenoxolone to the external solution inhibited cAMP uptake. Both cell depolarization and lowered extracellular Ca2+ increase the open probability of non-junctional hemichannels. Accordingly, the SpIH current augmentation was induced by the uptake of extracellular cAMP via open membrane hemichannels in Cx43 and Cx26 expressing cells. The data presented here show that hemichannels of Cx43 and Cx26 are permeable to cAMP, and further the data suggest that hemichannels are, in fact, a potential pathway for cAMP mediated cell-to-cell signaling.

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“…For example: 1) a report by Ohkubo and co-workers (13) suggests that the ecto-AMP phosphohydrolase activity of NG108 -15 cells (cell line formed by fusing mouse neuroblastoma cells with rat glioma cells) is mediated by TNAP rather than CD73; 2) studies by Zhang and colleagues (23) demonstrate that 5=-AMP suppresses synaptic transmission similarly in brain slices from CD73ϩ/ϩ vs. CD73Ϫ/Ϫ mice and that TNAP inhibition attenuates the effects of 5=-AMP only in CD73Ϫ/Ϫ brain slices; 3) Kuzhikandathil and co-workers (11) report that in the rat kidney 3=,5=-cAMP downregulates renal D1 receptor expression via a mechanism that is partially sensitive to the TNAP inhibitor levamisole; and 4) Pettengill et al (14) report that both CD73 and TNAP are importantly involved in the generation of adenosine from 5=-AMP in human blood, particularly in neonatal blood. However, the role of CD73 vs. TNAP in the renal production of adenosine remains an open question.…”

Section: Discussionmentioning

confidence: 99%

Interactive roles of CD73 and tissue nonspecific alkaline phosphatase in the renal vascular metabolism of 5′-AMP

Jackson

Cheng

Verrier

et al. 2014

American Journal of Physiology-Renal Physiology

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-CD73 metabolizes extracellular 5=-AMP to adenosine; yet recent experiments in brain tissue suggest that CD73 is not required for the metabolism of 5=-AMP to adenosine because of tissue nonspecific alkaline phosphatase (TNAP), which like CD73 is a GPI-anchored ecto-enyzme with 5=-nucleotidase activity. Because adenosine importantly regulates renovascular function, we investigated whether both TNAP and CD73 are involved in the renovascular metabolism of 5=-AMP. To test this, we examined in isolated, perfused mouse kidneys the metabolism of 5=-AMP (applied to the lumen of the renal vasculature via intrarenal artery administration) to adenosine by measuring renal venous levels of 5=-AMP, adenosine, and inosine (adenosine metabolite) by mass spectrometry. In one study, we compared 5=-AMP metabolism in naive CD73ϩ/ϩ (wild-type, n ϭ 16) vs. CD73Ϫ/Ϫ (knockout, n ϭ 16) kidneys; and in a second study, we compared 5=-AMP metabolism in CD73ϩ/ϩ (n ϭ 9) vs. CD73Ϫ/Ϫ (n ϭ 8) kidneys pretreated with levamisole (1 mmol/l; TNAP inhibitor). In naive kidneys, 5=-AMP increased renal venous 5=-AMP, adenosine, and inosine, and these responses were similar in CD73ϩ/ϩ vs. CD73Ϫ/Ϫ kidneys. Levamisole per se did not inhibit renovascular 5=-AMP metabolism; however, in the presence of levamisole, 5=-AMP increased renal venous 5=-AMP threefold more in CD73Ϫ/Ϫ vs. CD73ϩ/ϩ kidneys and knockout of CD73 inhibited 5=-induced adenosine and inosine by 81 and 86%, respectively. TNAP mRNA, protein, and activity were similar in CD73ϩ/ϩ vs. CD73Ϫ/Ϫ kidneys. In conclusion, CD73 and TNAP play interactive roles to metabolize luminally applied 5=-AMP in the renal vasculature such that inhibition of both is required to inhibit the production of adenosine.CD73; tissue nonspecific alkaline phosphatase; adenosine; inosine; 5=-AMP CD73 IS A GLYCOSYLPHOSPHATIDYLINOSITOL (GPI)-anchored ecto-5=-nucleotidase that resides on the cell surface and in most organ systems is critically involved in the conversion of extracellular 5=-AMP to adenosine (4). With regard to the kidney, CD73 participates in the production of adenosine that mediates tubuloglomerular feedback (3), provides renoprotective adenosine that renders the kidneys more able to tolerate acute ischemia-reperfusion (5), and produces adenosine in response to chronic exposure to angiotensin II leading to A 2B receptorinduced chronic renal disease and hypertension (24). Surprisingly, however, preliminary experiments suggest that when exogenous 5=-AMP is delivered into the renal artery, the resulting increase in renal venous adenosine is normal in CD73Ϫ/Ϫ kidneys (9). Since adenosine output measured in the renal vein after administration of 5=-AMP into the renal artery likely reflects largely renovascular metabolism of adenosine, these findings suggest that alternative pathways of adenosine production may participate in the metabolism of 5=-AMP to adenosine in the luminal aspect of the renal vasculature. If true, this is an important concept because of the powerful renovascular effects of adenosine (21).Like CD7...

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The Extracellular cAMP-Adenosine Pathway Regulates Expression of Renal D1 Dopamine Receptors in Diabetic Rats

Cited by 9 publications

References 44 publications

The 2′,3′-cAMP-adenosine pathway

The 2′,3′-cAMP-adenosine pathway

Cyclic nucleotide permeability through unopposed connexin hemichannels

Interactive roles of CD73 and tissue nonspecific alkaline phosphatase in the renal vascular metabolism of 5′-AMP

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