Substance P suppresses GABAA receptor function via protein kinase C in primary sensory neurones of bullfrogs.

Yamada, Kei; Akasu, Takashi

doi:10.1113/jphysiol.1996.sp021697

Cited by 31 publications

(20 citation statements)

References 40 publications

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“…SP has been shown to excite neurons through suppression of GIRK channel activity (23,43,44), which is believed to be mediated by activation of the G q -PLC-PKC signaling pathway (25,31,45). If this is the case, mutation of the PKC phosphorylation sites should abolish the GIRK inhibition by SP.…”

Section: Resultsmentioning

confidence: 99%

Molecular basis for the inhibition of G protein-coupled inward rectifier K⁺channels by protein kinase C

Mao

Wang²,

Chen³

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

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G protein-coupled inward rectifier K ؉ (GIRK) channels regulate cellular excitability and neurotransmission. The GIRK channels are activated by a number of inhibitory neurotransmitters through the G protein ␤␥ subunit (G␤␥) after activation of G protein-coupled receptors and inhibited by several excitatory neurotransmitters through activation of phospholipase C. If the inhibition is produced by PKC, there should be PKC phosphorylation sites in GIRK channel proteins. To identify the PKC phosphorylation sites, we performed systematic mutagenesis analysis on GIRK4 and GIRK1 subunits expressed in Xenopus oocytes. Our data showed that the heteromeric GIRK1͞GIRK4 channels were inhibited by a PKC activator phorbol 12-myristate 13-acetate (PMA) through reduction of single channel open-state probability. Direct application of the catalytic subunit of PKC to excised patches had a similar inhibitory effect. This inhibition was greatly eliminated by mutation of Ser-185 in GIRK1 and Ser-191 in GIRK4 that remained G protein sensitive. The PKC-dependent phosphorylation seems to mediate the channel inhibition by the excitatory neurotransmitter substance P (SP) as specific PKC inhibitors and mutation of these PKC phosphorylation sites abolished the SP-induced inhibition of GIRK1͞GIRK4 channels. Thus, these results indicate that the PKC-dependent phosphorylation underscores the inhibition of GIRK channels by SP, and Ser-185 in GIRK1 and Ser-191 in GIRK4 are the PKC phosphorylation sites.play an important role in controlling membrane excitability and synaptic transmission (1, 2). Four members of GIRK channels have been cloned in mammals, i.e., GIRK1 through GIRK4 (Kir3.1 through Kir3.4). These channels are expressed in the heart, brain, and endocrine tissues (3, 4). Stoichiometric studies indicate that a functional GIRK channel consists of four homomeric subunits or two pairs of heteromeric subunits (3, 4). Coassembly of GIRK1 with GIRK4 forms muscarinic receptorcoupled K ϩ channels mainly in the heart (2, 5). The GIRK channels are activated by certain inhibitory transmitters and hormones. On activation of G i/o -coupled receptors by the neurotransmitters or hormones, the G protein ␤␥ subunit (G ␤␥ ) dissociated from the heterotrimeric G ␣␤␥ directly interacts with cytosolic domains of GIRK channel proteins (6-9), and activates the channels through a mechanism that involves movement of pore-lining helices (10-12). Critical domains and amino acids have been identified to be responsible for the basal G ␤␥ -dependent and agonist-induced channel activities (6,7,13,14). Furthermore, the GIRK channel activation may rely on local phosphatidylinositol-4,5-biphosphate (PIP 2 ) in membrane microdomains (15, 16) or cytosolic Na ϩ (16,17).In addition to direct activation by G ␤␥ , GIRK channels are inhibited by a number of excitatory neurotransmitters or hormones, such as acetylcholine (18-20), thyroid-stimulating hormone (TSH)-releasing hormones (21), bombesin (22), substance P (SP) (23), and glutamate (24). These transmitters or hormones sh...

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Section: Resultsmentioning

confidence: 99%

Molecular basis for the inhibition of G protein-coupled inward rectifier K⁺channels by protein kinase C

Mao

Wang²,

Chen³

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

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“…Similar to opioid receptors, the inhibitory GABA A receptor is modulated by phosphorylation status (73)(74)(75). Both cholecystokinin and substance P decrease inhibitory GABA A currents via PKCdependent phosphorylation of the receptor (74)(75)(76).…”

Section: B the Primary Afferent-spinal Cord Synapsementioning

confidence: 99%

Protein kinase C in pain: Involvement of multiple isoforms

Velázquez

Mohammad

Sweitzer

2007

Pharmacological Research

130

125

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Pain is the primary reason that people seek medical care. At present chronic unremitting pain is the third greatest health problem after heart disease and cancer. Chronic pain is an economic burden in lost wages, lost productivity, medical expenses, legal fees and compensation. Chronic pain is defined as a pain of greater than two months duration and can be of an inflammatory or neuropathic origin that can arise following nerve injury or in the absence of any apparent injury. Chronic pain is characterized by an altered pain perception that includes allodynia (a response to a normally nonnoxious stimuli), and hyperalgesia (an exaggerated response to a normally noxious stimuli). This type of pain is often insensitive to the traditional pain drugs or surgical intervention and thus the study of the cellular and molecular mechanisms that contribute to chronic pain are of the up-most importance for the development of a new generation of analgesic agents. Protein kinase C isozymes are under investigation as potential therapeutics for the treatment of chronic pain conditions. The anatomical localization of protein kinase C isozymes in both peripheral and central nervous system sites that process pain have made them the topic of basic science research for close to two decades. This review will outline the research to date on protein kinase C involvement in pain and analgesia. In addition, this review will try to synthesize these works to begin to develop a comprehensive mechanistic understanding of how protein kinase C may function as the master regulator of peripheral and central sensitization that underlies many chronic pain conditions.

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“…40 The GABA A ␤ and ␥-subunits are, in turn, targets for a number of protein kinases, such as PKC. 41 Furthermore, the SP-GABA A receptor coupling in frog dorsal root ganglia (DRG) 42 was mediated by PKC. We therefore investigated whether the PKC activator PMA mimicked the whole-cell effects of SP.…”

Section: Sp-gaba a Inhibition Is Pkc Dependentmentioning

confidence: 99%

“…64 We knew of no previous reports of SP acting by this mechanism in brain slices, however a similar mechanism was proposed for the SP inhibition of GABA A current in frog DRG neurons. 42 We therefore sought to investigate whether tachykinins interacted with GABA A receptors of PVN parvocellular neurons. We find that SP does indeed powerfully inhibit GABA A receptors.…”

Section: Inhibition Of Gaba a Ion Channels By Spmentioning

confidence: 99%

Substance P Targets Sympathetic Control Neurons in the Paraventricular Nucleus

Womack

Morris

Gent

et al. 2007

Circulation Research

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Abstract-The paraventricular nucleus (PVN) contains spinally-projecting neurons implicated in fine-tuning the cardiovascular system. In vivo activity of "presympathetic" parvocellular neurons is suppressed by tonic inhibition from GABA-ergic inputs, inhibition of which increases sympathetic pressor activity and heart rate. Targeting of this specific neuronal population could potentially limit elevations of heart rate and blood pressure associated with disease. Here we show, for the first time, that "presympathetic" PVN neurons are disinhibited by the neuropeptide substance P (SP) acting via tachykinin NK1 receptor inhibition of GABA A currents. Application of SP to the paraventricular nucleus of rats increases heart rate and blood pressure. Key Words: cardiovascular control Ⅲ GABA Ⅲ substance P T he parvocellular subdivision of the hypothalamic paraventricular nucleus (PVN) contains both hypothalamicpituitary-adrenal axis control neurons, and spinally-projecting cardiovascular control neurons. [1][2][3][4][5][6] Estimates suggest that up to 2000 neurons project directly from the PVN to the intermediolateralis (IML) of the spinal cord. 7-9 These projecting parvocellular neurons have been implicated in a number of facets of cardiovascular control. For example, circadian regulation of blood pressure, 10 blood-volume regulation, 7,8 and the cardiovascular response to psychological stress. 11 Furthermore, elevated sympathetic activity is associated with congestive heart failure observed in humans and animals, 12-14 and rat models suggest that this is associated with a diminished GABA sensitivity of PVN neurons. 13,15,16 As such, spinally-projecting PVN neurons are prime targets for therapeutic intervention with the cardiovascular system.Although there have been, to date, few in vitro studies detailing cellular mechanisms potentially exploitable for therapeutic control of cardiovascular PVN neurons, there have been a number of, largely in vivo, studies investigating their basic control and physiological activity. Early in vivo electrophysiological studies on cats confirmed an anticipated monosynaptic connection between the PVN and spinal sympathetic motor area (the IML). 17 Furthermore, stimulation (electrical or glutamate) of the PVN was shown to give rise to an extremely rapid rise of blood pressure and renal sympathetic outflow in conscious rats. 18 Additional studies show that in vivo, the PVN receives tonic inhibition from GABAergic inputs and this maintains their activity at relatively low levels, 19 -21 despite the fact that these neurons also receive excitatory glutaminergic inputs. 18 Strikingly, excitation of this nucleus by glutamate, or by blockade of GABA A receptors with the antagonist bicuculline, increases blood pressure and heart rate. 18,22 Other physiological inputs to "presympathetic" parvocellular neurons have been, until now, unknown. Potentially, pharmacological inhibition of this neuronal population could limit sympathetically induced elevations of heart rate and blood pressure seen during hea...

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Substance P suppresses GABAA receptor function via protein kinase C in primary sensory neurones of bullfrogs.

Cited by 31 publications

References 40 publications

Molecular basis for the inhibition of G protein-coupled inward rectifier K⁺channels by protein kinase C

Molecular basis for the inhibition of G protein-coupled inward rectifier K⁺channels by protein kinase C

Protein kinase C in pain: Involvement of multiple isoforms

Substance P Targets Sympathetic Control Neurons in the Paraventricular Nucleus

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Substance P suppresses GABAA receptor function via protein kinase C in primary sensory neurones of bullfrogs.

Cited by 31 publications

References 40 publications

Molecular basis for the inhibition of G protein-coupled inward rectifier K+channels by protein kinase C

Molecular basis for the inhibition of G protein-coupled inward rectifier K+channels by protein kinase C

Protein kinase C in pain: Involvement of multiple isoforms

Substance P Targets Sympathetic Control Neurons in the Paraventricular Nucleus

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Product

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Molecular basis for the inhibition of G protein-coupled inward rectifier K⁺channels by protein kinase C

Molecular basis for the inhibition of G protein-coupled inward rectifier K⁺channels by protein kinase C