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Author(s): Patricia González-Rodríguez [sup.1] , Enrico Zampese [sup.1] , Kristen A. Stout [sup.1] , Jaime N. Guzman [sup.1] , Ema Ilijic [sup.1] , Ben Yang [sup.1] , Tatiana Tkatch [sup.1] [...], Loss of functional mitochondrial complex I (MCI) in the dopaminergic neurons of the substantia nigra is a hallmark of Parkinson's disease.sup.1. Yet, whether this change contributes to Parkinson's disease pathogenesis is unclear.sup.2. Here we used intersectional genetics to disrupt the function of MCI in mouse dopaminergic neurons. Disruption of MCI induced a Warburg-like shift in metabolism that enabled neuronal survival, but triggered a progressive loss of the dopaminergic phenotype that was first evident in nigrostriatal axons. This axonal deficit was accompanied by motor learning and fine motor deficits, but not by clear levodopa-responsive parkinsonism--which emerged only after the later loss of dopamine release in the substantia nigra. Thus, MCI dysfunction alone is sufficient to cause progressive, human-like parkinsonism in which the loss of nigral dopamine release makes a critical contribution to motor dysfunction, contrary to the current Parkinson's disease paradigm.sup.3,4. Dysfunction of mitochondrial complex I in mice is sufficient to cause progressive parkinsonism in which the loss of nigral dopamine release critically contributes to motor dysfunction.

Background [K.sup.+] channels of the TASK family are believed to participate in sensory transduction by chemoreceptor (glomus) cells of the carotid body (CB). However, studies on the systemic CB-mediated ventilatory response to hypoxia and hypercapnia in TASK1- and/or TASK3-deficient mice have yielded conflicting results. We have characterized the glomus cell phenotype of TASK-null mice and studied the responses of individual cells to hypoxia and other chemical stimuli. CB morphology and glomus cell size were normal in wild-type as well as in [TASK1.sup.-/-] or double [TASK1/3.sup.-/-] mice. Patch-clamped TASK1/3-null glomus cells had significantly higher membrane resistance and less hyperpolarized resting potential than their wild-type counterpart. These electrical parameters were practically normal in [TASK1.sup.-/-] cells. Sensitivity of background currents to changes of extracellular pH was drastically diminished in TASK1/3-null cells. In contrast with these observations, responsiveness to hypoxia or hypercapnia of either [TASK1.sup.-/-] or double [TASK1/3.sup.-/-] cells, as estimated by the amperometric measurement of catecholamine release, was apparently normal. TASK1/3 knockout cells showed an enhanced secretory rate in basal (normoxic) conditions compatible with their increased excitability. Responsiveness to hypoxia of TASK1/3-null cells was maintained after pharmacological blockade of maxi-[K.sup.+] channels. These data in the TASK-null mouse model indicate that TASK3 channels contribute to the background [K.sup.+] current in glomus cells and to their sensitivity to external pH. They also suggest that, although TASK1 channels might be dispensable for [O.sub.2]/C[O.sub.2] sensing in mouse CB cells, TASK3 channels (or TASK1/3 heteromers) could mediate hypoxic depolarization of normal glomus cells. The ability of [TASK1/3.sup.-/-] glomus cells to maintain a powerful response to hypoxia even after blockade of maxi-[K.sup.+] channels, suggests the existence of multiple sensor and/or effector mechanisms, which could confer upon the cells a high adaptability to maintain their chemosensory function. doi/10.1085/jgp.200910302

Hemeoxygenase-2 (HO-2) is an antioxidant enzyme that can modulate recombinant maxi-[K.sup.+] channels and has been proposed to be the acute [O.sub.2] sensor in the carotid body (CB). We have tested the physiological contribution of this enzyme to [O.sub.2] sensing using HO-2 null mice. HO-2 deficiency leads to a CB phenotype characterized by organ growth and alteration in the expression of stress-dependent genes, including the maxi-[K.sup.+] channel [alpha]-subunit. However, sensitivity to hypoxia of CB is remarkably similar in HO-2 null animals and their control littermates. Moreover, the response to hypoxia in mouse and rat CB cells was maintained after blockade of maxi-[K.sup.+] channels with iberiotoxin. Hypoxia responsiveness of the adrenal medulla (AM) (another acutely responding [O.sub.2]-sensitive organ) was also unaltered by HO-2 deficiency. Our data suggest that redox disregulation resulting from HO-2 deficiency affects maxi-[K.sup.+] channel gene expression but it does not alter the intrinsic [O.sub.2] sensitivity of CB or AM cells. Therefore, HO-2 is not a universally used acute [O.sub.2] sensor.

Voltage-gated [Ca.sup.2+] channels in arterial myocytes can mediate [Ca.sup.2+] release from the sarcoplasmic reticulum and, thus, induce contraction without the need of extracellular [Ca.sup.2+] influx. This metabotropic action of [Ca.sup.2+] channels (denoted as calcium-channel-induced calcium release or CCICR) involves activation of G proteins and the phospholipase C-inositol 1,4,5-trisphosphate pathway. Here, we show a form of vascular tone regulation by extracellular ATP that depends on the modulation of CCICR. In isolated arterial myocytes, ATP produced facilitation of [Ca.sup.2+]-channel activation and, subsequently, a strong potentiation of CCICR. The facilitation of L-type channel still occurred after full blockade of purinergic receptors and inhibition of G proteins with GDP[beta]S, thus suggesting that ATP directly interacts with [Ca.sup.2+] channels. The effects of ATP appear to be highly selective, because they were not mimicked by other nucleotides (ADP or UTP) or vasoactive agents, such as norepinephrine, acetylcholine, or endothelin-1. We have also shown that CCICR can trigger arterial cerebral vasoconstriction in the absence of extracellular calcium and that this phenomenon is greatly facilitated by extracellular ATP. Although, at low concentrations, ATP does not induce arterial contraction per se, this agent markedly potentiates contractility of partially depolarized or primed arteries. Hence, the metabotropic action of L-type [Ca.sup.2+] channels could have a high impact on vascular pathophysiology, because, even in the absence of Ca.sup.2+] channel opening, it might mediate elevations of cytosolic Ca.sup.2+] and contraction in partially depolarized vascular smooth muscle cells exposed to small concentrations of agonists. L-type [Ca.sup.2+] channel | vascular contractility | excitation-contraction coupling

The remarkable mechanisms by which different organs detect and respond to acute changes in oxygen tension is examined. The improved understanding of the mechanisms involved in the acute sensing of oxygen helps to explain the pathophysiology of idiopathic pulmonary arterial hypertension, persistent patent ductus arteriosus, and high-altitude pulmonary edema and gives insight into possible therapy.

Cellular mechanisms of oxygen sensing are discussed focusing on cells of mammals. Better understanding of cellular mechanisms of oxygen sensing will help in developing new medications to such diseases as stroke of myocardial ischemia cased by localized lack of oxygen. Complete molecular characterization of the hypoxia signaling pathways would be helpful in seeing differential sensitivities to hypoxia of the various cell types and the gradation of the cellular responses to variable levels of PO(sub.2).