Putative Neurotransmitters Research Articles

Oral administration of β‐alanine modifies carnosine concentrations in the muscles and brains of chickens

ABSTRACTCarnosine, and its derivative anserine, are known to function as anti‐oxidants and putative neurotransmitters. They are especially rich in the breast muscle (Musculus pectoralis superficialis, MPS) of chickens. To clarify whether the concentrations of carnosine and anserine are altered by dietary management, the effect of oral administration of their constituent, β‐alanine (β‐Ala), was determined in the MPS and brains of chickens. Birds were orally administered β‐Ala (22 mmol/kg) twice a day for five consecutive days (from 2 to 6 days old). In the MPS, carnosine was increased by β‐Ala, whereas anserine and taurine were decreased. The concentrations of other free amino acids in the MPS were also modified by β‐Ala. In the brain, the oral administration of β‐Ala increased anserine and carnosine and decreased taurine, but caused no changes to other free amino acid concentrations. These results suggest that orally administered β‐Ala increases carnosine concentrations in both the MPS and brains of chickens. However, the effects of β‐Ala on other concentrations differ depending on the tissues.

Binding of [ 3H]MK-801 in subcellular fractions of Schistosoma mansoni: Evidence for interaction with nicotinic receptors

Several studies have suggested that l-glutamate is a putative neurotransmitter in Schistosoma mansoni. Recently, we detected the presence of low-affinity binding sites for [ 3H]kainic acid in the heterogeneous (P 1) subcellular fraction of S. mansoni. In an attempt to characterize N-methyl- d-aspartate (NMDA) receptors in this worm, we performed binding assays with [ 3H]MK-801, a NMDA non-competitive antagonist, in the P 1 fraction of adult S. mansoni. In competition experiments, MK-801 (IC 50 ∼200 μM) and ketamine (IC 50 ∼500 μM) exhibited a low affinity for the sites labeled with [ 3H]MK-801. Along with the lack of modulation of this binding by glutamatergic agonists and antagonists and the absence of stereoselectivity for MK-801 isomers, these results suggest that [ 3H]MK-801 could label a site different from the classical NMDA receptor in S. mansoni. Based on the evidences that MK-801 interacts with mammalian muscle and central nervous system nicotinic receptors as a low-affinity noncompetitive antagonist, we have investigated the effects of MK-801 on the nicotine-induced flaccid paralysis of the worm, in vivo. The motility of S. mansoni was quantified by image analysis through a measure of displacement of the worm's extremities. In the presence of (−)-nicotine (10–100 μM), we observed an immediate paralysis of the worms, that was inhibited by 1 mM MK-801. Besides nicotine, choline (10–50 mM) was also able to inhibit the worm's motility. As a conclusion, we suggest that [ 3H]MK-801 binds to nicotinic receptors, and not NMDA receptors, in subcellular fractions of S. mansoni.

The use of the rat isolated vagus nerve for functional measurements of the effect of drugs in vitro

In this article we describe how to dissect, set up and use the rat isolated vagus nerve in a ‘grease gap’ apparatus which provides a simple and practical method for measuring the effects of drugs on the membrane potential of axons in the nerve in vitro. Some discussion of the origins and development of the technique as well as the strengths and disadvantages of the preparation as a neuropharmacological tool are included. The vagus nerve conducts action potentials in at least three distinct types of axons that can be measured extracellularly as compound action potentials and distinguished on the basis of their conduction velocity and excitability. Activity in myelinated A fibres and unmyelinated C fibres can be measured separately easily. The axons express receptors for a wide range of putative neurotransmitter agents including 5-HT, GABA and ATP as well as other agents such as capsaicin, anandamide, bradykinin and prostanoids. Responses to all of these chemicals can be measured as a depolarization of the nerve fibres. The vagus nerve is an important target for a wide range of drugs and the isolated preparation provides a fairly simple preparation for studying their effects. The isolated vagus nerve is also a convenient system in which the effects of drugs that have been discovered using heterologous expression systems can be assayed on receptors and ion channels that are expressed in a native neural system.

Protective effect of rhynchophylline and isorhynchophylline on in vitro ischemia-induced neuronal damage in the hippocampus: putative neurotransmitter receptors involved in their action

Rhynchophylline and isorhynchophylline are major tetracyclic oxindole alkaloid components of Uncaira species, which have been long used as medicinal plants. In this study we examined the protective effects of rhynchophylline and isorhynchophylline on in vitro ischemia-induced neuronal damage in the hippocampus and interaction of these alkaloids with neurotransmitter receptors in a receptor expression model of Xenopus oocytes. In vitro ischemia was induced by exposing the hippocampal slices to oxygen- and D-glucose-deprived medium over 8 min. The resultant neuronal damage was elucidated as deterioration of population spike (PS) amplitudes evoked trans-synaptically by electrical stimulation of Schäffer collaterals and recorded in the CA1 area. Rhynchophylline and isorhynchophylline, as well as the N-methyl-D-aspartate (NMDA) antagonist (±)-2-amino-5-phosphono-valeric acid (APV), the muscarinic M 1 receptor antagonist pirenzepine, and the 5-HT 2 receptor antagonist ketanserin, attenuated the in vitro ischemia-induced neuronal damage in a concentration-dependent manner. There was no difference in the extent of protection against the neuronal damage between rhynchophylline and isorhynchophylline treatment. In Xenopus oocytes expressing the rat brain receptors encoded by total RNA, both rhynchophylline and isorhynchophylline reduced muscarinic receptor- and 5-HT 2 receptor-mediated current responses in a competitive manner. Together with our previous findings that rhynchophylline and isorhynchophylline have a non-competitive antagonistic effect on the NMDA-type ionotropic glutamate receptors, the present results suggest that these alkaloids exert their protective action against ischemia-induced neuronal damage by preventing NMDA, muscarinic M 1, and 5-HT 2 receptors-mediated neurotoxicity during ischemia.

D-Serine as a putative glial neurotransmitter.

Abundant recent evidence favors a neurotransmitter/neuromodulator role for D-serine. D-serine is synthesized from L-serine by serine racemase in astrocytic glia that ensheath synapses, especially in regions of the brain that are enriched in NMDA-glutamate receptors. D-serine is more potent than glycine at activating the 'glycine' site of these receptors. Moreover, selective degradation of D-serine but not glycine by D-amino acid oxidase markedly reduces NMDA neurotransmission. D-serine appears to be released physiologically in response to activation by glutamate of AMPA-glutamate receptors on D-serine-containing glia. This causes glutamate-receptor-interacting protein, which binds serine racemase, to stimulate enzyme activity and D-serine release. Thus, glutamate triggers the release of D-serine so that the two amino acids can act together on postsynaptic NMDA receptors. D-serine also plays a role in neural development, being released from Bergmann glia to chemokinetically enhance the migration of granule cell cerebellar neurons from the external to the internal granular layer.

Survival of trauma-injured neurons in rat brain by treatment with proline-rich peptide (PRP-1): an immunohistochemical study.

The objective of this immunohistochemical research was to reveal the distribution of a proline-rich peptide-1 (PRP-1) in various brain structures of intact and trauma-injured rats and to identify the mechanisms of promotion of neuronal recovery processes following PRP-1 treatment. PRP-1, produced by bovine hypothalamic magnocellular cells and consisting of 15 amino acid residues, is a fragment of neurophysin vasopressin associated glycoprotein isolated from bovine neurohypophysis neurosecretory granules. PRP-1-immunoreactivity (PRP-1-IR) was detected in the brain of intact rats in the neurons of paraventricular (PVN) and supraoptic (SON) nuclei in the hypothalamus, in almost all cell groups in the medulla oblongata, in Purkinje and some cerebellar nuclei cells, and in nerve fibers. At 3 weeks after hemisection of the spinal cord (SC) an asymmetry of PRP-1 localization in the PVN and SON was observed: no PRP-1-IR was exhibited at the affected sides of both nuclei. Daily intramuscular administration of PRP-1 for 3 weeks significantly increased the number of PRP-1-immunoreactive (PRP-1-Ir) varicose nerve fibers, and cells in PVN and SON and in cell groups of the limbic system and brain stem. Tanycytes in the median eminence and covering ependyma also demonstrated strong PRP-1-IR. PRP-1 treatment also activated neuropeptide Y-IR (NPY-IR) in nerve fibers and immunophilin fragment-IR (IphF-IR) in lymphocytes and nerve cells. A strong increase of PRP-1-IR was observed in the PVN and SON of SC-injured rats following the treatment with another PRP (PRP-3). Preliminary physiological data demonstrate that PRP-3 is more "aggressive" in the recovery processes than PRP-1. Based on the findings regarding PRP action on neurons survival, axons regeneration, and the number of IphF-Ir lymphocytes and NPY-Ir nerve fibers, PRP is suggested to act as a neuroprotector, functioning as a putative neurotransmitter and immunomodulator.

Galanin receptors and actions

Galanin is a neuropeptide and putative neurotransmitter that is expressed by neurons in the brain, spinal cord and ganglia of the peripheral autonomic nervous system. Three cloned receptor subtypes mediate the actions ofgalanin. Galanin is generally inhibitory at the level of single neuronal elements in the nervous system. Binding of galanin to its receptors on neuronal cell bodies leads to elevated potassium conductance, membrane hyperpolarization and suppression of excitability. Activation of galaninergic receptors at transmitter release sites on axons inhibits the release of neurotransmitter and suppresses synaptic transmission. Emergent effects of the two inhibitory actions at the integrated circuit level of organization include alterations in cognition and memory in the brain, involvement in the processing of nociceptive information in the spinal cord and alterations of motility and secretory beharior in the gastrointestinal tract. The galanin receptor subtypes are logical drug targets for development of selective agonists and antagonists.

Brain cholinesterases: I. The clinico-histopathological and biochemical basis of Alzheimer's disease

Substantial evidence is presented demonstrating that it is the cholinesterases (ChEs) that constitute the organizer, the connector and the safeguard for multiple neurochemical functions and mature anatomical architecture of the brain. In Alzheimer's disease (AD), the histopathological characteristics are initially and primarily associated with the degeneration of the acetylcholinesterase (AChE) system in various brain regions. Multiple classic and/or putative neurotransmitters and neuromodulators, virtually all the peptide hormones of the endocrine and neuroendocrine systems in the brain, their specific synthesizing and hydrolyzing marker enzymes and associated uptake processes (transporters), and receptors, do not actually participate in the formation of senile plaques and neurofibrillary tangles in the brains of patients suffering from AD. The massive perturbation in different neurochemicals seen in AD is essentially caused by the ChEs-associated pathology. The graded patterns of brain ChEs expression affect the preferential vulnerability and severity of the AD clinico-pathologic presentation. It seems that the common law in nature may also dominate the destiny of brain ChEs system, i.e., the weaker the cells express AChE, the more susceptible the cells are to AD degeneration, and vice versa.

Autonomic microganglion cells: a source of acetylcholine in the rat carotid body.

Hypoxic chemosensitivity of peripheral arterial chemoreceptors and the ventilatory response to O2 deprivation increases with postnatal development. Multiple putative neurotransmitters, which are synthesized in the carotid body (CB), are thought to mediate signals generated by hypoxia. Acetylcholine (ACh) is believed to be a major excitatory neurotransmitter participating in hypoxic chemosensitivity. However, it is not known whether ACh originates from type I cells in the CB. In these studies, we tested the hypothesis that choline acetyltransferase (ChAT) and vesicular ACh transporter (VAChT) mRNAs are expressed in the CB and that mRNA levels would increase with postnatal maturation or exposure to hypoxia. Semiquantitative in situ hybridization histochemistry and immunohistochemistry were used to localize cholinergic markers within neurons and cells of the rat CB, the nodose-petrosal-jugular ganglion complex, and the superior cervical ganglion up to postnatal day 28. We show that the pattern of distribution, in tissue sections, is similar for both ACh markers; however, the level of VAChT mRNA is uniformly greater than that of ChAT. VAChT mRNA and immunoreactivity are detected abundantly in the nodose-petrosal-jugular ganglion complex in a number of microganglion cells embedded in nerve fibers innervating the CB for all postnatal groups, whereas ChAT mRNA is detected in only a few of these cells. Contrary to our hypothesis, postnatal maturation caused a reduction in ACh trait expression, whereas hypoxic exposure did not induce the upregulation of VAChT and ChAT mRNA levels in the CB, microganglion, or within the ganglion complex. The present findings indicate that the source of ACh in the CB is likely within autonomic microganglion cells and cholinergic nerve terminals.

Neuropharmacokinetic and dynamic studies of agmatine (decarboxylated arginine).

Agmatine has been previously proposed to represent a novel neurotransmitter. One of the criteria required to test that hypothesis is that the exogenously administered chemical produces pharmacological effects similar to the physiological effects of the putative neurotransmitter. Since agmatine was first identified in brain, approximately sixty studies of the in vivo effects of exogenously administered agmatine have been reported. Despite the assertion that agmatine functions as a neuromodulator/neurotransmitter, the vast majority of experiments have administered agmatine through systemic (rather than central) routes of administration. Systemic delivery of agmatine for studies of centrally mediated phenomenon (e.g., pain, spinal cord injury, cardiovascular responses) relies on the presumption that agmatine (a polar compound) gains appreciable access to the CNS. The mechanism by which agmatine crosses the blood-brain barrier is not well understood. A number of studies have examined the in vivo effects of agmatine following central administration (e.g., intracerebroventricular and intrathecal). This paper summarizes and provides a comparison between the systemic versus central routes of administration for delivery of agmatine in experimental subjects.

The regulation of circadian rhythms in the fly’s visual system: involvement of FMRFamide-like neuropeptides and their relationship to pigment dispersing factor in Musca domestica and Drosophila melanogaster

The cross-sectional area of axon profiles in two classes of interneuron, L1 and L2, in the fly’s lamina, exhibits a circadian rhythm of swelling and shrinking; axon caliber also changes after microinjecting putative lamina neurotransmitters. Among these, the neuropeptide pigment-dispersing factor, PDF, is proposed to transmit circadian information from the housefly’s ( Musca domestica) clock to L1 and L2, increasing axon caliber during the day. Testing whether other neurotransmitters may modulate this effect we have: (1) examined optic lobe cell immunoreactivity to FMRFamide peptides and its co-immunolocalization to PDF in M. domestica and Drosophila melanogaster, and to the product of the circadian clock gene PER in D. melanogaster; and (2) made microinjections of FMRFamide and related neuropeptides into the second neuropil, or medulla. In M. domestica, nine groups of optic lobe cells, several cells in the lateral and dorsal protocerebrum, and in the subesophageal ganglion, together contribute dense FMRFamide immunoreactive arborizations in almost all central brain and optic lobe neuropils. In D. melanogaster a similar pattern of labeling arises from fewer cells. Daytime microinjections show that another neuropeptide, similar to molluscan FMRFamide, shrinks M. domestica’s L1 and L2 axons, thus opposing the action of PDF. We discuss evidence for a medulla site of action for a released FMRFamide-like peptide, either from: MeRF2 cells, acting directly on L1 and L2’s medulla terminals; or MeRF1 cells, acting indirectly via medulla centrifugal cells C2 and C3.

Carbon Monoxide Neurotransmission Activated by CK2 Phosphorylation of Heme Oxygenase-2

Carbon monoxide (CO) is a putative gaseous neurotransmitter that lacks vesicular storage and must be synthesized rapidly following neuronal depolarization. We show that the biosynthetic enzyme for CO, heme oxygenase-2 (HO2), is activated during neuronal stimulation by phosphorylation by CK2 (formerly casein kinase 2). Phorbol ester treatment of hippocampal cultures results in the phosphorylation and activation of HO2 by CK2, implicating protein kinase C (PKC) in CK2 stimulation. Odorant treatment of olfactory receptor neurons augments HO2 phosphorylation and activity as well as cyclic guanosine monophosphate (cGMP) levels, with all of these effects selectively blocked by CK2 inhibitors. Likewise, CO-mediated nonadrenergic, noncholinergic (NANC) relaxation of the internal anal sphincter requires CK2 activity. Our findings provide a molecular mechanism for the rapid neuronal activation of CO biosynthesis, as required for a gaseous neurotransmitter.

Neural pathways mediating vaginal function: the vagus nerves and spinal cord oxytocin.

The initial observations, made in our laboratory with Knut Larsson, of the ability of vaginocervical stimulation (VCS) to block withdrawal responses to foot pinch in rats has led to findings of multiple behavioral, autonomic, and neuroendocrine effects of this potent stimulus in rats and also in women. It has led to an understanding of: (1) the neuroanatomical and neurochemical basis of a novel and potent pain-blocking mechanism; (2) likely neuroanatomical pathways mediating both the Ferguson reflex and a specific autonomic response - the pupil-dilating effect of VCS; (3) a role for oxytocin as a putative central nervous system neurotransmitter that stimulates autonomic sympathetic preganglionic neurons within the spinal cord; and (4) a novel pathway that can convey sensory activity from the cervix, adequate to induce orgasm, via the vagus nerves. This latter pathway bypasses the spinal cord and projects directly to the medulla oblongata, and thus can convey genital afferent activity despite complete spinal cord injury at any level.

Two approaches to double post-embedding immunogold labeling of freeze-substituted tissue embedded in low temperature Lowicryl HM20 resin

Double labeling is used for localizing two antigens simultaneously in the same tissue. We have used two approaches to post-embedding immunogold labeling to investigate whether nerve terminals in the guinea-pig anteroventral cochlear nucleus (AVCN) that contain γ-aminobutyric acid (GABA) or glycine are capable of retrieving the other amino acid as part of an investigation of colocalization of these putative neurotransmitters. For this, vibroslices of perfusion-fixed brain stem were freeze-substituted and embedded in the low temperature resin, Lowicryl HM20. Simultaneous labeling of ultrathin sections was then performed with a mixture of a rabbit primary antibody to GABA and a guinea-pig primary antibody to the glycine transporter, GLYT2, followed by labeling with a mixture of secondary antibodies (goat anti-rabbit IgG-30 nm gold, goat anti-guinea pig IgG-15 nm gold). This approach indicated that GLYT2 occurs in the plasma membrane of some terminals that contain GABA. The other approach involved sequential labeling of ultrathin sections with a rabbit primary antibody to the GABA transporter, GAT1, followed by an anti-rabbit secondary antibody conjugated to 15-nm gold particles. Sections were then treated with paraformaldehyde vapor to denature any free anti-IgG binding sites on the first antibody, and labeled with a primary antibody to glycine also raised in rabbit followed by an anti-rabbit secondary antibody conjugated to 30-nm gold particles. This approach indicated that GAT1 occurs in the plasma membrane of some terminals that contain glycine. Thus, these techniques can be used to localize heat-labile multiple antigens in the same tissue.

N‐, α‐, and β‐Substituted 3‐Aminopropionic Acids: Design, Syntheses and Antiseizure Activities.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Gastrointestinal motility and the brain‐gut axis

The role of the brain‐gut axis in gastrointestinal motility is discussed according to the specific organs of the gastrointestinal tract. Not only clinical studies but basic animal research are reviewed. Although the mechanism of functional gut disorders remains to be clarified, recent data suggest that there is evidence that the brain‐gut axis has significant effects on gastrointestinal motility. The major role of endoscopy in the diagnosis of functional gastrointestinal disorders is to exclude organic gastrointestinal disorders. In the esophagus, the lower esophageal sphincter and a gamma‐aminobutyric acid B mechanism are considered to play important roles in gastroesophageal reflux disease. In the stomach, corticotropin‐releasing factor, neuropeptide Y and other substances might be involved in the pathogenesis of non‐ulcer dyspepsia. In the small intestine, corticotropin‐releasing factor, gamma‐aminobutyric acid B and other substances are considered to modulate intestinal transit via central mechanisms. In the colon, it is known that psychiatric factors are related to the onset and clinical course of irritable bowel syndrome. Serotonin, corticotropin‐releasing factor, gamma‐aminobutyric acid, orphanin FQ and neuropeptide Y have been reported as putative neurotransmitters. More efforts in basic science studies and animal and human studies of physiology of the gastointestinal tract are still required. These efforts will elucidate further mechanisms to clarify the etiology of motility disorders and encourage the investigation of new therapies in this field.

Metabotropic glutamate receptors activate phospholipase D in astrocytes through a protein kinase C-dependent and Rho-independent pathway

Metabotropic glutamate receptors (mGluRs) are G protein-coupled receptors that mediate phospholipase D (PLD) activation in brain, but the mechanism underlying this response remains unclear. Here we used primary cultures of astrocytes as a cell model to explore the mechanism that links mGluRs to PLD. Glutamate activated both phospholipase C (PLC) and PLD with equal potency and this effect was mimicked by l-cysteinesulfinic acid, a putative neurotransmitter previously shown to activate mGluRs coupled to PLD, but not PLC, in adult brain. PLD activation by glutamate was dependent on Ca 2+ mobilization and fully blocked by both protein kinase C (PKC) inhibitors and PKC down-regulation, suggesting that PLD activation is secondary to PLC stimulation. Furthermore, brefeldin A, an inhibitor of ADP-ribosylation factor (ARF) activation, partially inhibited the activation of PLD by glutamate. By contrast, pretreatment of astrocytes with Clostridium difficile toxin B, which inactivates small G proteins of the Rho family (Rho, Rac, and Cdc42), had no effect on PLD stimulation by glutamate. Taken together, these results indicate that PLD activation by mGluRs in astrocytes is dependent on PKC and small G proteins of the ARF family, but does not require Rho proteins.

Agmatine induces anxiolysis in the elevated plus maze task in adult rats

Agmatine is an endogenous released polyamine recently proposed to be a putative neurotransmitter, however its physiological role is still to be determined. We investigated the hypothesis that agmatine, systemically administered to adult Wistar rats, might exert anxiolytic-like behavior in the elevated plus maze (EPM) and the open field. Agmatine (1, 10, 20, 40 and 100 mg/kg) and saline were administered i.p. 30 min before the EPM and the open field. Administration of agmatine (20 and 40 mg/kg) increased the time spent in the open arms of the EPM, as compared to the saline group, with no effect on locomotion activity in the open field. However, 100 mg/kg of agmatine significantly reduced the number of entries into enclosed arms of the EPM and the total number of crossings in the open field. We suggest that agmatine, in doses of 20 and 40 mg/kg, causes a mild anxiolytic-like behavior and discuss the possibility that this first reported effect could be caused either by the inhibition of nitric oxide synthase, the blockage of NMDA receptors or by the activation of alpha-2-adrenoceptors.

Peroxynitrite and caspase-3 expression after ischemia/reperfusion in mouse cardiac arrest model.

NO is a putative neurotransmitter and neuromodulator in the brain. NO is not functioning as a direct neurotoxin. NO with the superoxide radical product peroxynitrite (ONOO-) is much more cytotoxic under tissue impairment conditions. Caspase-3, a potent effector of apoptosis that is triggered via several different signaling pathways, may play a very important role in neuronal cell death caused by various brain injuries. The relationship between mouse caspase-3 and peroxynitrite remains unclear. In the present study, we examined the in vivo expression of 3-nitrotyrosine (a metabolite of peroxinitrite) and caspase-3 after cerebral ischemia produced in a global ischemia model using mice (i.e., a cardiac arrest model). 3-nitrotyrosine immunoreactivity was detected in neuronal cells in the hippocampal dentate nucleus, and cortical regions starting at 12 hrs after ischemia. In particular, numerous neuronal cells were highly immunoreactive for 3-nitrotyrosine in the cortical regions. In hippocampal CA1 pyramidal neurons, 3-nitrotyrosine immunoreactivity was detected from 24 hrs. Caspase-3 immunopositive cells were observed in approximately the same area in which the positive reaction to the anti-nitrotyrosine antibody was observed. These results provide direct evidence for the induction of 3-nitrotyrosine and caspase-3 expression in vivo in an ischemia model using mice. The present findings suggest that peroxynitrite generated by cerebral ischemia/ reperfusion was strongly cytotoxic and induced neuronal cell death (apoptosis) mediated by caspase-3.

Regulation of K+ currents by CO in carotid body type I cells and pulmonary artery smooth muscle cells.

Potassium channels are a diverse group of proteins that control membrane excitability and their regulation can influence cell signalling through the modulation of calcium entry. A subset of these channels appears to be particularly sensitive to oxygen tension and these play an important role in the regulation of arterial blood gas tensions. In pulmonary arterial smooth muscle cells, K+ channel activity is linked to contractile tone. Factors that regulate the activity of these channels therefore have a major influence upon blood vessel diameter and therefore on pulmonary artery (PA) blood pressure, thus altering regional ventilation -perfusion ratios in the lung. In carotid body (CB) type I cells, K+ channel activity is linked to the secretion of a variety of putative neurotransmitter and regulation of these channels therefore influences carotid sinus nerve activity and thus cardiorespiratory control. In both systems, hypoxia decreases the activity of a variety of K+ channels, some of which regulate the resting membrane potential. In CB type I cells and in PA smooth muscle cells, hypoxia decreases the activity of the TASK-1 channel (a background K+ channels in type one cells and probably KN channels in PA (Gurney et al.2002)), large conductance Ca2+-activated (BKca) channels and/or voltage-activated (Kv) channels depending on species and experimental conditions (Lopez-Barneo et al.2001).