Dopamine D2 Receptor Modulation of K+ Channel Activity Regulates Excitability of Nucleus Accumbens Neurons at Different Membrane Potentials

2006 ◽  
Vol 96 (5) ◽  
pp. 2217-2228 ◽  
Author(s):  
Mariela F. Perez ◽  
Francis J. White ◽  
Xiu-Ti Hu
Keyword(s):  
Nucleus Accumbens ◽  
Dopamine D2 Receptor ◽  
D2 Receptor ◽  
Brain Slices ◽  
Membrane Potentials ◽  
Inward Rectification ◽  
K Channel ◽  
Channel Activity ◽  
Receptor Modulation ◽  
Intracellular Ca

The nucleus accumbens (NAc) is a forebrain area in the mesocorticolimbic dopamine (DA) system that regulates many aspects of drug addiction. Neuronal activity in the NAc is modulated by different subtypes of DA receptors. Although DA signaling has received considerable attention, the mechanisms underlying D2-class receptor (D2R) modulation of firing in medium spiny neurons (MSNs) localized within the NAc remain ambiguous. In the present study, we performed whole cell current-clamp recordings in rat brain slices to determine whether and how D2R modulation of K+ channel activity regulates the intrinsic excitability of NAc neurons in the core region. D2R stimulation by quinpirole or DA significantly and dose-dependently decreased evoked Na+ spikes. This D2R effect on inhibiting evoked firing was abolished by antagonism of D2Rs, reversed by blockade of voltage-sensitive, slowly inactivating A-type K+ currents ( IAs), or eliminated by holding membrane potentials at levels in which IAs was inactivated. It was also mimicked by inhibition of cAMP-dependent protein kinase (PKA) activity, but not phosphatidylinositol-specific phospholipase C (PI-PLC) activity. Moreover, D2R stimulation also reduced the inward rectification and depolarized the resting membrane potentials (RMPs) by decreasing “leak” K+ currents. However, the D2R effects on inward rectification and RMP were blocked by inhibition of PI-PLC, but not PKA activity. These findings indicate that, with facilitated intracellular Ca2+ release and activation of the D2R/Gq/PLC/PIP2 pathway, the D2R-modulated changes in the NAc excitability are dynamically regulated and integrated by multiple K+ currents, including but are not limited to IAs, inwardly rectifying K+ currents ( IKir), and “leak” currents ( IK-2P).

scholarly journals Histamine hyperpolarizes human glioblastoma cells by activating the intermediate-conductance Ca2+-activated K+ channel

2009 ◽  
Vol 297 (1) ◽  
pp. C102-C110 ◽  
Author(s):  
Bernard Fioretti ◽  
Luigi Catacuzzeno ◽  
Luigi Sforna ◽  
Francesco Aiello ◽  
Francesca Pagani ◽  
...  
Keyword(s):  
Driving Force ◽  
Inward Rectification ◽  
K Channel ◽  
Channel Activity ◽  
Pharmacological Profile ◽  
Human Glioblastoma ◽  
Physiological Conditions ◽  
Parsimonious Explanation ◽  
Unitary Conductance ◽  
Intracellular Ca

The effects of histamine on the membrane potential and currents of human glioblastoma (GL-15) cells were investigated. In perforated whole cell configuration, short (3 s) applications of histamine (100 μM) hyperpolarized the membrane by activating a K+-selective current. The response involved the activation of the pyrilamine-sensitive H1 receptor and Ca2+ release from thapsigargin-sensitive intracellular stores. The histamine-activated current was insensitive to tetraethylammonium (3 mM), iberiotoxin (100 nM), and d-tubocurarine (100 μM) but was markedly inhibited by charybdotoxin (100 nM), clotrimazole (1 μM), and 1-[(2-chlorophenyl)diphenylmethyl]-1H-pyrazole (TRAM-34, 1 μM), a pharmacological profile congruent with the intermediate conductance Ca2+-activated K+ (IKCa) channel. Cell-attached recordings confirmed that histamine activated a K+ channel with properties congruent with the IKCa channel (voltage independence, 22 pS unitary conductance and slight inward rectification in symmetrical 140 mM K+). More prolonged histamine applications (2–3 min) often evoked a sustained IKCa channel activity, which depended on a La2+ (10 μM)-sensitive Ca2+ influx. Intracellular Ca2+ measurements revealed that the sustained IKCa channel activity enhanced the histamine-induced Ca2+ signal, most likely by a hyperpolarization-induced increase in the driving force for Ca2+ influx. In virtually all cells examined we also observed the expression of the large conductance Ca2+-activated K+ (BKCa) channel, with a unitary conductance of ca. 230 pS in symmetrical 140 mM K+, and a Ca2+ dissociation constant [ KD(Ca)] of ca. 3 μM, at −40 mV. Notably in no instance was the BKCa channel activated by histamine under physiological conditions. The most parsimonious explanation based on the different KD(Ca) for the two KCa channels is provided.

Dopamine D2 Receptor-Activated Ca2+ Signaling Modulates Voltage-Sensitive Sodium Currents in Rat Nucleus Accumbens Neurons

2005 ◽  
Vol 93 (3) ◽  
pp. 1406-1417 ◽  
Author(s):  
Xiu-Ti Hu ◽  
Yan Dong ◽  
Xu-Feng Zhang ◽  
Francis J. White
Keyword(s):  
Nucleus Accumbens ◽  
Neuronal Excitability ◽  
Dopamine D2 Receptor ◽  
D2 Receptor ◽  
Brain Diseases ◽  
Sodium Currents ◽  
Intracellular Ca ◽  
Muscarinic Cholinergic ◽  
Rat Nucleus Accumbens ◽  
Stimulation Of

Receptor-mediated dopamine (DA) modulation of neuronal excitability in the nucleus accumbens (NAc) has been shown to be critically involved in drug addiction and a variety of brain diseases. However, the mechanisms underlying the physiological or pathological molecular process of DA modulation remain largely elusive. Here, we demonstrate that stimulation of DA D2 class receptors (D2R) enhanced voltage-sensitive sodium currents (VSSCs, INa) in freshly dissociated NAc neurons via suppressing tonic activity of the cyclic AMP/PKA cascade and facilitating intracellular Ca2+ signaling. D2R-mediated INa enhancement depended on activation of Gi/o proteins and was mimicked by direct inhibition of PKA. Furthermore, increasing free [Ca2+]in by activating inositol 1,4,5-triphosphate receptors (IP3Rs), blocking Ca2+ reuptake, or adding buffered Ca2+, all enhanced INa. Under these circumstances, D2R-mediated INa enhancement was occluded. In contrast, D2R-mediated INa enhancement was blocked by inhibition of IP3Rs, chelation of free Ca2+, or inhibition of Ca2+/calmodulin-activated calcineurin (CaN), but not by inhibition of phospholipase C (PLC). Although stimulation of muscarinic cholinergic receptors (mAChRs) also increased INa, this action was blocked by PLC inhibitors. Our findings indicate that D2Rs mediate an enhancement of VSSCs in NAc neurons, in which cytosolic free Ca2+ plays a crucial role. Our results also suggest that D2R-mediated reduction in tonic PKA activity may increase free [Ca2+]in, primarily via disinhibition of IP3Rs. IP3R activation then facilitates Ca2+ signaling and subsequently enhances VSSCs via decreasing PKA-induced phosphorylation and increasing CaN-induced dephosphorylation of Na+ channels. This study provides insight into the complex and dynamic role of D2Rs in the NAc.

scholarly journals Haloperidol ameliorates androgen-induced behavioral deficits in developing male rats

2018 ◽  
Vol 237 (2) ◽  
pp. 193-205 ◽  
Author(s):  
Chunxiao Qi ◽  
Xiaoming Ji ◽  
Guoliang Zhang ◽  
Yunxiao Kang ◽  
Yuanxiang Huang ◽  
...  
Keyword(s):  
Nucleus Accumbens ◽  
Motor Behavior ◽  
Dopamine D2 Receptor ◽  
D2 Receptor ◽  
Neuropsychiatric Disorders ◽  
Male Rats ◽  
Neural Basis ◽  
Childhood Onset ◽  
Early Postnatal Development ◽  
Androgen Exposure

The purpose of present study was to infer the potential effects of testosterone increase in some male-based childhood-onset neuropsychiatric disorders, such as Tourette syndrome. Thus, the influence of early postnatal androgen exposure upon the neurobehaviors and its possible neural basis were investigated in the study. Male pup rats received consecutive 14-day testosterone propionate (TP) subcutaneous injection from postnatal day (PND) 7. The TP treatment produced the hyperactive motor behavior and grooming behavior as well as the increased levels of dopamine, tyrosine hydroxylase and dopamine transporter in the mesodopaminergic system and the elevated levels of serotonin in the nucleus accumbens, without affecting the levels of glutamate, γ-aminobutyric acid, norepinephrine and histamine in the caudate putamen and nucleus accumbens of PND21 and PND49 rats. Dopamine D2 receptor antagonist haloperidol was administered to the early postnatal TP-exposed PND21 and PND49 male rats 30 min prior to open field test. Haloperidol significantly ameliorated the motor behavioral and grooming behavioral defects induced by early postnatal TP exposure. The results demonstrated that early postnatal androgen exposure significantly disturbed the brain activity of developing male rats via enhancing the mesodopaminergic activity. It was suggested that abnormal increments of testosterone levels during the early postnatal development might be a potential risk factor for the incidence of some male-based childhood-onset neuropsychiatric disorders by affecting the mesodopaminergic system.

scholarly journals Expression of a dopamine D2 receptor-activated K+ channel on identified striatopallidal and striatonigral neurons

1998 ◽  
Vol 95 (19) ◽  
pp. 11440-11444 ◽  
Author(s):  
B. L. Waszczak ◽  
L. P. Martin ◽  
G. J. Greif ◽  
J. E. Freedman
Keyword(s):  
Dopamine D2 Receptor ◽  
D2 Receptor ◽  
K Channel ◽  
Dopamine D2

No evidence for dependence of early cortical auditory processing on dopamine D2-receptor modulation: a whole-head magnetoencephalographic study

2001 ◽  
Vol 107 (2) ◽  
pp. 117-123 ◽  
Author(s):  
Seppo Kähkönen ◽  
Jyrki Ahveninen ◽  
Eero Pekkonen ◽  
Seppo Kaakkola ◽  
Juha Huttunen ◽  
...  
Keyword(s):  
Auditory Processing ◽  
Dopamine D2 Receptor ◽  
D2 Receptor ◽  
Dopamine D2 ◽  
Receptor Modulation ◽  
Cortical Auditory Processing

scholarly journals Immune Checkpoint Inhibitors Regulate K+ Channel Activity in Cytotoxic T Lymphocytes of Head and Neck Cancer Patients

2021 ◽  
Vol 12 ◽  
Author(s):  
Vaibhavkumar S. Gawali ◽  
Ameet A. Chimote ◽  
Hannah S. Newton ◽  
Manuel G. Feria-Garzón ◽  
Martina Chirra ◽  
...  
Keyword(s):  
T Cell ◽  
Ion Channel ◽  
Head And Neck ◽  
Immune Checkpoint ◽  
Cell Function ◽  
K Channel ◽  
Channel Activity ◽  
Crac Channels ◽  
T Cell Function ◽  
Intracellular Ca

Programmed death receptor-1 (PD-1) and its ligand (PD-L1) interaction negatively regulates T cell function in head and neck squamous cell carcinoma (HNSCC). Overexpression of PD-1 reduces intracellular Ca2+ fluxes, and thereby T cell effector functions. In HNSCC patients, PD-1 blockade increases KCa3.1 and Kv1.3 activity along with Ca2+ signaling and mobility in CD8+ peripheral blood T cells (PBTs). The mechanism by which PD-L1/PD-1 interaction regulates ion channel function is not known. We investigated the effects of blocking PD-1 and PD-L1 on ion channel functions and intracellular Ca2+ signaling in CD8+ PBTs of HNSCC patients and healthy donors (HDs) using single-cell electrophysiology and live microscopy. Anti-PD-1 and anti-PD-L1 antibodies increase KCa3.1 and Kv1.3 function in CD8+ PBTs of HNSCC patients. Anti-PD-1 treatment increases Ca2+ fluxes in a subset of HSNCC patients. In CD8+ PBTs of HDs, exposure to PD-L1 reduces KCa3.1 activity and Ca2+ signaling, which were restored by anti-PD-1 treatment. The PD-L1-induced inhibition of KCa3.1 channels was rescued by the intracellular application of the PI3 kinase modulator phosphatidylinositol 3-phosphate (PI3P) in patch-clamp experiments. In HNSCC CD8+ PBTs, anti-PD-1 treatment did not affect the expression of KCa3.1, Kv1.3, Ca2+ release activated Ca2+ (CRAC) channels, and markers of cell activation (CD69) and exhaustion (LAG-3 and TIM-3). Our data show that immune checkpoint blockade improves T cell function by increasing KCa3.1 and Kv1.3 channel activity in HNSCC patients.

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