Reaction to stress requires feedback adaptation of cellular functions to secure a response without distress, but the molecular order of this process is only partially understood. Here, we report a previously unrecognized regulatory element in the general adaptation syndrome. Kir6.2, the ion-conducting subunit of the metabolically responsive ATP-sensitive potassium (KATP) channel, was mandatory for optimal adaptation capacity under stress. Genetic deletion of Kir6.2 disrupted KATP channel-dependent adjustment of membrane excitability and calcium handling, compromising the enhancement of cardiac performance driven by sympathetic stimulation, a key mediator of the adaptation response. In the absence of Kir6.2, vigorous sympathetic challenge caused arrhythmia and sudden death, preventable by calcium-channel blockade. Thus, this vital function identifies a physiological role for KATP channels in the heart. I on channels control the electrical potential across the cell membrane of all living organisms. The profile of channel expression within the cell is defined by evolution through natural selection (1, 2). Developed as channel͞enzyme multimers, K ATP channels combine properties of two different classes of protein to adjust rapidly and precisely membrane excitability according to the metabolic state of the cell (3-7). Identified in metabolically active tissues of a broad range of species, K ATP channels were discovered originally in heart muscle where they are expressed in high density (8, 9). Functional cardiac K ATP channels can be formed only through physical association of the pore-forming Kir6.2 subunit with the regulatory sulfonylurea receptor SUR2A (10-12). In this complex, which harbors an intrinsic ATPase activity, nucleotide interaction at SUR2A gates potassium permeation through Kir6.2, a property believed to be responsible for the fine metabolic modulation of membrane potential-dependent cellular functions (7,(13)(14)(15)(16).The physiological role of K ATP channels as metabolic sensors has been understood best in the regulation of hormone secretion in pancreatic ␤-cells and more recently in the hypothalamus (17-21). In the heart, definition of the function of this protein complex thus far has been limited to acute protection against ischemic events (22). In fact, under ischemia, the opening of as few as 1% of K ATP channels is sufficient to produce significant shortening of the cardiac action potential (23), manifested globally by ST-segment elevation on the electrocardiogram (24). Yet, beyond the impact in pathophysiology, a physiological role for the cardiac K ATP channel that supports its maintenance in hearts of many species is lacking (25).The general adaptation syndrome is a ubiquitous reaction vital for self-preservation under conditions of stress such as exertion or fear (26-28). Mediated by a catecholamine surge, this syndrome generates an alteration of physiologic and biochemical functions to sustain a superior level of bodily performance and allows confrontation or escape in response to threat...

MR imaging can be used to detect, localize, and stage transition zone prostate cancers.

Transduction of energetic signals into membrane electrical events governs vital cellular functions, ranging from hormone secretion and cytoprotection to appetite control and hair growth. Central to the regulation of such diverse cellular processes are the metabolism sensing ATP-sensitive K ؉ (KATP) channels. However, the mechanism that communicates metabolic signals and integrates cellular energetics with K ATP channel-dependent membrane excitability remains elusive. Here, we identify that the response of KATP channels to metabolic challenge is regulated by adenylate kinase phosphotransfer. Adenylate kinase associates with the KATP channel complex, anchoring cellular phosphotransfer networks and facilitating delivery of mitochondrial signals to the membrane environment. Deletion of the adenylate kinase gene compromised nucleotide exchange at the channel site and impeded communication between mitochondria and K ATP channels, rendering cellular metabolic sensing defective. Assigning a signal processing role to adenylate kinase identifies a phosphorelay mechanism essential for efficient coupling of cellular energetics with K ATP channels and associated functions. D elivery of metabolic signals to intracellular compartments is a critical determinant of cellular homeostasis. In particular, efficient communication between cellular energetics and membrane metabolic sensors is required for regulation of cell excitability and associated functions (1, 2). Plasmalemmal ATPsensitive K ϩ (K ATP ) channels, formed by the Kir6.2 potassium channel and the sulfonylurea receptor (SUR), are unique nucleotide sensors that adjust membrane potential in response to intracellular metabolic oscillations (2-5). Transition of the SUR subunit from the ATP to the ADP-liganded state promotes K ϩ permeation through Kir6.2 and defines K ATP channel activity (5-7). However, the mechanism that facilitates nucleotide exchange in the K ATP channel environment and promotes coupling of membrane electrical events with cellular metabolic pathways remains unknown.Cellular phosphotransfer reactions catalyze nucleotide exchange facilitating communication between sites of ATP generation and ATP utilization (8-11). In this way, the phosphotransfer enzyme adenylate kinase (AK) amplifies metabolic signals and promotes intracellular phosphoryl transfer by catalyzing the reaction ATP ϩ AMP 7 2ADP (12, 13). Adenylate kinase has a distinct signaling role in setting the cellular response to stress through activation of AMP-dependent processes (12-15). Deletion of the major AK isoform (AK1) results in disturbed muscle energetic economy and decreased tolerance to metabolic stress (14, 15). Mutations in AK compromise nucleotide export from mitochondria (16), as well as the function of ATP-binding cassette transporters (17). Conversely, stimulation of AK phosphotransfer promotes nucleotide-dependent membrane functions (18,19). However, the actual significance of AK phosphotransfer in communicating energetic signals to membrane metabolic sensors, such as the K ATP cha...

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from surgical pathology as organ-confined cancer of ≤ 0.5 cm 3 with no poorly differentiated elements. The accuracy of predicting insignificant prostate cancer was assessed using areas under receiver operating characteristic curves (AUCs), for previously reported clinical models and for newly generated MR models combining clinical variables, and biopsy data with MRI data (MRI model) and MRI/MRSI data (MRI/MRSI model). RESULTSAt pathology, 41% of patients had insignificant cancer; both MRI (AUC 0.803) and MRI/MRSI (AUC 0.854) models incorporating clinical, biopsy and MR data performed significantly better than the basic (AUC 0.574) and more comprehensive medium (AUC 0.726) clinical models. The P values for the differences between the models were: base vs medium model, < 0.001; base vs MRI model, < 0.001; base vs MRI/MRSI model, < 0.001; medium vs MRI model, < 0.018; medium vs MRI/MRSI model, < 0.001. CONCLUSIONSThe new MRI and MRI/MRSI models performed better than the clinical models for predicting the probability of insignificant prostate cancer. After appropriate validation, the new MRI and MRI/MRSI models might help in counselling patients who are considering choosing deferred therapy.

PURPOSE:To prospectively evaluate magnetic resonance (MR) imaging and MR spectroscopy for depiction of local prostate cancer recurrence after external-beam radiation therapy, with stepsection pathologic findings as the standard of reference. MATERIALS AND METHODS:Study received institutional approval, and written informed consent was obtained. Study was compliant with Health Insurance Portability and Accountability Act. Sextant biopsy, digital rectal examination, MR imaging, MR spectroscopy, and salvage radical prostatectomy with step-section pathologic examination were performed in nine patients with increasing prostate-specific antigen levels after external-beam radiation therapy. MR imaging criterion for tumor was a focal nodular region of reduced signal intensity at T2-weighted imaging. MR spectroscopic criteria for tumor were voxels with choline (Cho) plus creatine (Cr) to citrate (Cit) ratio ([Cho + Cr]/Cit) of at least 0.5 or voxels with detectable Cho and no Cit in the peripheral zone. Sensitivity and specificity of sextant biopsy, digital rectal examination, MR imaging, and MR spectroscopy were determined by using a prostate sextant as the unit of analysis. For feature analysis, MR imaging and MR spectroscopic findings were correlated with step-section pathologic findings. RESULTS:MR imaging and MR spectroscopy showed estimated sensitivities of 68% and 77%, respectively, while sensitivities of biopsy and digital rectal examination were 48% and 16%, respectively. MR spectroscopy appears to be less specific (78%) than the other three tests, each of which had a specificity higher than 90%. MR spectroscopic feature analysis showed that a metabolically altered benign gland could be falsely identified as tumor by using MR spectroscopic criteria; further analysis of MR spectroscopic features did not lead to improved MR spectroscopic criteria for recurrent tumor. CONCLUSION:In summary, MR imaging and MR spectroscopy may be more sensitive than sextant biopsy and digital rectal examination for sextant localization of cancer recurrence after external-beam radiation therapy.

Although ischemic preconditioning induces bioenergetic tolerance and thereby remodels energy metabolism that is crucial for postischemic recovery of the heart, the molecular components associated with preservation of cellular energy production, transfer, and utilization are not fully understood. Here myocardial bioenergetic dynamics were assessed by 18 O-assisted 31 P-NMR spectroscopy in control or preconditioned hearts from wild-type (WT) or Kir6. In contrast with WT hearts, preconditioning failed to preserve contractile recovery in Kir6.2-KO hearts, as tight coupling between postischemic performance and high-energy phosphoryl transfer was compromised in the KATP-channel-deficient myocardium. Thus intact KATP channels are integral in ischemic preconditioning-induced protection of cellular energetic dynamics and associated cardiac performance.ATP-sensitive K ϩ channel; cardioprotection; ischemia; metabolism ATP-SENSITIVE K ϩ (K ATP ) channels, which are highly expressed in myocardial sarcolemma, serve as membrane metabolic sensors that translate fluctuations in cellular energetics into regulation of electrical activity (1, 24,25,40). Nucleotide-dependent K ϩ permeation through Kir6.2, the inwardly rectifying pore-forming core of the K ATP channel, is gated by ATPase activity of the regulatory subunit SUR2A integrated with cellular metabolism through phosphotransfer networks (1, 2, 4, 13, 33, 42). This metabolic sensor function is underscored in response to ischemic challenge, where sarcolemmal K ATP channels have been proposed to respond to changes in cellular energetics that regulate ionic homeostasis (1,5,11,15, 24,25).In fact, Kir6.2-knockout (Kir6.2-KO) hearts, which lack functional K ATP channels, display a compromised ability to regulate electrical activity with loss of characteristic ST-segment elevation on the ECG during ischemia and poor contractile recovery (19,35). Furthermore, intact sarcolemmal K ATP channel function contributes to the reduction of infarct size afforded by ischemic preconditioning (IPC) (35), a cardioprotective phenomenon by which brief intermittent periods of ischemia protect the myocardium against a prolonged ischemic insult (21). Essential in the IPC-induced injury-tolerant state is the remodeling of energy transduction and cellular phosphotransfer networks, which results in maintained bioenergetic homeostasis and improved contractile recovery (10,22,26,29). Metabolic flux through creatine kinase, the major phosphotransfer enzyme in the myocardium and integrator of cellular metabolism with K ATP channels (1, 31), tightly correlates with cardioprotection of preconditioning (26). Although this correlation suggests a relationship between metabolic sensor activity and preservation of energetic homeostasis, it remains unexplored whether cardiac K ATP channels are required for IPC-mediated protection of cellular bioenergetics.Here, 18O-assisted 31 P-NMR spectroscopy captures bioenergetic dynamics in hearts from wild-type (WT) and Kir6.2-KO mice. Deletion of sarcolemmal K ATP channels ...

ATP-sensitive potassium (K ATP ) channels are required for maintenance of homeostasis during the metabolically demanding adaptive response to stress. However, in disease, the effect of cellular remodeling on K ATP channel behavior and associated tolerance to metabolic insult is unknown. Here, transgenic expression of tumor necrosis factor a induced heart failure with typical cardiac structural and energetic alterations. In this paradigm of disease remodeling, K ATP channels responded aberrantly to metabolic signals despite intact intrinsic channel properties, implicating defects proximal to the channel. Indeed, cardiomyocytes from failing hearts exhibited mitochondrial and creatine kinase de®cits, and thus a reduced potential for metabolic signal generation and transmission. Consequently, K ATP channels failed to properly translate cellular distress under metabolic challenge into a protective membrane response. Failing hearts were excessively vulnerable to metabolic insult, demonstrating cardiomyocyte calcium loading and myo®brillar contraction banding, with tolerance improved by K ATP channel openers. Thus, disease-induced K ATP channel metabolic dysregulation is a contributor to the pathobiology of heart failure, illustrating a mechanism for acquired channelopathy. Keywords: ATP-sensitive potassium channel/energy metabolism/heart failure/potassium channel openers/ TNFa