Xiang Qian, MD, PhD, is a Pain Management Physician and Clinical Professor of Anesthesiology, Perioperative and Pain Medicine at Stanford University. He is also the inaugural Stanford Medicine Endowed Director.
Dr. Qian is highly respected for his work on developing novel therapies for various chronic pain conditions, and he lectures internationally for those work and topics. Dr. Qian’s clinical interests include the treatment of acute and chronic pain, with special interest in migraine, headache, trigeminal neuralgia, glossopharyngeal neuralgia, hemifacial spasm, atypical facial pain, cancer pain, back pain, joint pain, nerve pain, and others. At Stanford, Dr. Qian developed many advanced surgical and interventional technologies for his patients, and he currently leads the CT-guided interventional pain program and is the recipient of Translational and Clinical Innovation Award at Stanford.
With his deep interest in clinical innovation and translational medicine, Dr. Qian is the faculty professor of Stanford Wearable Electronics Initiative (eWEAR) and has been working with colleagues from engineering school to develop mini implantable nerve stimulator, powered by wireless energy. Similar to a pacemaker for the heart, nerve stimulators are modulators for the nerves.
Due to his passion for global health and leadership experience, Dr. Qian was appointed as the Medical Director of Stanford International Medical Services (IMS) since 2016, where he has been working in collaboration with faculty members from all subspecialties and hospital administrations to help deliver care for international patients and promote international collaborations. His vision is to help Stanford become the leader in international medicine by providing its physicians and faculty the opportunities to expand their practice internationally and spread knowledge globally.
Dr. Qian completed his residency and fellowship training at Stanford. Prior to that, he received his PhD degree in Physiology and Biophysics from University of Miami Miller School of Medicine, and went through Postdoc fellowship training in Neuroscience at UCSF. Outside of the work he does at Stanford, Dr. Qian founded the Chinese American Physicians’ Society to foster his efforts in bringing medical knowledge internationally. Today, the society has more than 600 physician members from 50 states of the US, across over 38 different subspecialties.
In his free time, Dr. Qian enjoys reading, running, hiking and exploring the mountains and beaches of Northern California.
- Pain Management
- Facial pain
- Migraine and headache
- Trigeminal Neuralgia and Glossopharyngeal neuralgia
- Hemifacial Spasm
- Cancer Pain
- Spine and Back Pain
- Neuropathic Pain
- Interventional Surgery
- CT-guided Procedure
Clinical Professor, Anesthesiology, Perioperative and Pain Medicine
Clinical Professor (By courtesy), Neurosurgery
Advisory Board, Stanford eWEAR Initiative (2021 - Present)
Co-Director, Stanford Facial Pain Program (2018 - Present)
Medical Director, International Medical Services-Stanford Health Care (2016 - Present)
Committee, Stanford Clinical Competency Committee, Pain Medicine (2014 - Present)
Associate Medical Director, International Medical Services-Stanford Health Care (2014 - 2016)
Honors & Awards
Faculty Teaching Award, Stanford (2021)
Fok Ying-Tung Medal, WACD (2019)
Translational and Clinical Innovation Award, Stanford Medicine (2017)
Injectable Electrostimulators, Stanford-Coulter Translational Research Grants (2014)
HHMI Postdoc fellowship, UCSF (2008)
Award of MDA Grant for Neurotransmission Study, Muscular Dystrophy Association (2004)
Award of Academic Merit, University of Miami School of Medicine (2003)
First Prize Award, The 11th Annual Neuroscience Research Day, University of Miami (2002)
Predoctoral Fellowship Grant Award, American Heart Association (AHA) (2001-2003)
Residency: Stanford University Anesthesiology Residency (2012) CA
Board Certification: American Board of Anesthesiology, Pain Medicine (2013)
Board Certification: American Board of Anesthesiology, Anesthesia (2013)
Fellowship: Stanford University Hospital - Pain Medicine (2013) CA
Board Certification, Pain Management, American Board of Anesthesiology, Pain Medicine (2013)
Board Certification, American Board of Anesthesiology, Anesthesia (2013)
Internship, Metrowest Medical Center/Harvard Medical School Affiliated Program, MA (2009)
Postgraduate, University of California at San Francisco, Neuroscience (2008)
Medical Education: University of Miami (2003) FL
Current Research and Scholarly Interests
Migraine and headache
Trigeminal Neuralgia and Glossopharyngeal neuralgia
CT guided Procedure
-Facial Nerve neuralgia and neuropathy
CT guided awake RFA of facial nerve
-Medical device development
-AI based headache diagnosis and management
-CT guided intervention
-Intra-nasal endoscopy guided procedure
-Mechanisms of neuropathic pain
-Ion channel and diseases
-Neurotoxicity of anesthetics
Treatment Efficacy and Technical Advantages of Temporary Spinal Nerve Root Stimulation Compared to Traditional Spinal Cord Stimulation for Postherpetic Neuralgia.
2022; 25 (6): E863-E873
BACKGROUND: Postherpetic neuralgia (PHN) is a common complication after herpes zoster infection. While conventional dorsal column temporary spinal cord stimulation (tSCS) has been shown as an effective treatment option for this pain condition, recent data suggests ipsilateral temporary spinal nerve root stimulation (tSNRS) as a safe alternative for treating PHN. However, there is no direct clinical comparison between the newer tSNRS and the traditional tSCS.OBJECTIVES: The current retrospective study aimed to describe the technical factors and the therapeutic efficacy of tSNR for patients with unilateral PHN and to compare these parameters with those treated with tSCS.STUDY DESIGN: Retrospective cohort study.SETTING: Single-center study in a large academic hospital.METHODS: One hundred sixty patients with unilateral PHN who underwent 7-14 days of tSCS (n = 109) or tSNRS (n = 51) treatment were included. Technical factors between the 2 groups, such as procedure time, radiation dosage, number of electrodes used, number of stimulation parameter adjustments, and average cost, were compared. Treatment efficacy, measured by analgesic coverage, pain visual analog scale (VAS), total analgesic agent consumption, Pittsburgh sleep quality index (PSQI), and physical and mental quality of life, were also compared between the 2 groups at baseline, post-procedure, and 3 months after stimulation treatment.RESULTS: Patients who underwent tSNRS reported significant improvement in pain level, sleep quality, and overall quality of life immediately postprocedure and during the follow-up period. This therapeutic effect was comparable to the tSCS group. Moreover, tSNRS achieved this therapeutic effect with a fewer number of implanted electrodes and stimulation adjustments than tSCS. The precision and consistency of the tSNRS technique were associated with a significant overall lower cost, a shorter procedure time, and less intraoperative radiation exposure in the tSNRS group than in those who received tSCS.LIMITATIONS: The current retrospective cohort study was limited by its relatively short follow-up period. Also, the selection of stimulation techniques was not randomized.CONCLUSIONS: While tSNRS provides similar therapeutic efficacy compared to tSCS for patients with unilateral PHN; it offers several technical advantages. These advantages include shorter procedure time, less radiation exposure, fewer implanted electrodes, more effective stimulation, and lower overall cost.
View details for PubMedID 36122270
The Molecular Basis and Pathophysiology of Trigeminal Neuralgia.
International journal of molecular sciences
2022; 23 (7)
Trigeminal neuralgia (TN) is a complex orofacial pain syndrome characterized by the paroxysmal onset of pain attacks in the trigeminal distribution. The underlying mechanism for this debilitating condition is still not clearly understood. Decades of basic and clinical evidence support the demyelination hypothesis, where demyelination along the trigeminal afferent pathway is a major driver for TN pathogenesis and pathophysiology. Such pathological demyelination can be triggered by physical compression of the trigeminal ganglion or another primary demyelinating disease, such as multiple sclerosis. Further examination of TN patients and animal models has revealed significant molecular changes, channelopathies, and electrophysiological abnormalities in the affected trigeminal nerve. Interestingly, recent electrophysiological recordings and advanced functional neuroimaging data have shed new light on the global structural changes and the altered connectivity in the central pain-related circuits in TN patients. The current article aims to review the latest findings on the pathophysiology of TN and cross-examining them with the current surgical and pharmacologic management for TN patients. Understanding the underlying biology of TN could help scientists and clinicians to identify novel targets and improve treatments for this complex, debilitating disease.
View details for DOI 10.3390/ijms23073604
View details for PubMedID 35408959
Awake CT-guided percutaneous stylomastoid foramen puncture and radiofrequency ablation of facial nerve for treatment of hemifacial spasm.
Journal of neurosurgery
Hemifacial spasm (HFS) is a debilitating neuromuscular disorder with limited treatment options. The current study describes a novel minimally invasive procedure that provided effective and sustained relief for patients with HFS. The authors provide a detailed description of the awake CT-guided percutaneous radiofrequency ablation (RFA) of the facial nerve for treatment of HFS, and they examine its clinical efficacy. This is the first time in the literature that this procedure has been applied and systematically analyzed for HFS.Patients with a history of HFS were recruited between August 2018 and April 2020. Those with a history of cerebellopontine lesions, coagulopathy, ongoing pregnancy, cardiac pacemaker or defibrillator implants, or who declined the procedure were excluded from the study. Fifty-three patients who met the study criteria were included and underwent awake CT-guided RFA. Under minimal sedation, a radiofrequency (RF) needle was used to reach the stylomastoid foramen on the affected side under CT guidance, and the facial nerve was localized using a low-frequency stimulation current. Patients were instructed to engage facial muscles as a proxy for motor monitoring during RFA. Ablation stopped when the patients' hemifacial contracture resolved. Patients were kept for inpatient monitoring for 24 hours postoperatively and were followed up monthly to monitor resolution of HFS and complications for up to 19 months.The average duration of the procedure was 32-34 minutes. Postoperatively, 91% of the patients (48/53) had complete resolution of HFS, whereas the remaining individuals had partial resolution. A total of 48 patients reported mild to moderate facial paralysis immediately post-RFA, but most resolved within 1 month. No other significant complication was observed during the study period. By the end of the study period, 5 patients had recurrence of mild HFS symptoms, whereas only 2 patients reported dissatisfaction with the treatment results.The authors report for the first time that awake CT-guided RFA of the facial nerve at the stylomastoid foramen is a minimally invasive procedure and can be an effective treatment option for HFS.
View details for DOI 10.3171/2020.10.JNS203209
View details for PubMedID 33862595
Efficacy and Safety of Awake CT-guided Percutaneous Balloon Compression of Trigeminal Ganglion for Trigeminal Neuralgia.
Pain medicine (Malden, Mass.)
To describe the method and clinical efficacy of awake CT-guided percutaneous balloon compression (PBC) as a treatment for trigeminal neuralgia (TN).In this case-series, TN patients were treated with awake CT-guided PBC and followed for treatment efficacy and complications for 12 months.A single-center study.66 patients with medical treatment-refractory TN were recruited for the study.The procedure was performed under moderate sedation. A balloon catheter was inserted through a trocar needle to reach Meckel's cavity under CT-guidance. The position and optimal shape of the contrast-filled balloon was confirmed with CT 3-dimension reconstruction. Compression of the TG was considered completed when the patient notified operators about facial hypoesthesia or the resolution of TN symptoms. All patients were followed up monthly for 12 months to monitor treatment efficacy and complications.The average TG compression time was 272±81 seconds, at which point the patients reported significant facial hypoesthesia comparing to the contralateral side or resolution of triggered pain in the affected area. All patients had resolution of TN symptoms for 6 months, with a 1-year recurrent rate of 13%. Overall safety profile is improved with the current technique. Side effects, such as hypoesthesia, and mastication weakness, were overall mild, and did not impact patients' quality-of-life. Some complications that were historically associated with PBC, such as diplopia and keratitis, were not present.This new awake CT-guided PBC technique produces better outcomes than the traditional PBC under fluoroscopy-guidance and general anesthesia.
View details for DOI 10.1093/pm/pnab228
View details for PubMedID 34320638
A Narrative Review on Perioperative Pain Management Strategies in Enhanced Recovery Pathways-The Past, Present and Future.
Journal of clinical medicine
2021; 10 (12)
Effective pain management is a key component in the continuum of perioperative care to ensure optimal outcomes for surgical patients. The overutilization of opioids in the past few decades for postoperative pain control has been a major contributor to the current opioid epidemic. Multimodal analgesia (MMA) and enhanced recovery after surgery (ERAS) pathways have been repeatedly shown to significantly improve postoperative outcomes such as pain, function and satisfaction. The current review aims to examine the history of perioperative MMA strategies in ERAS and provide an update with recent evidence. Furthermore, this review details recent advancements in personalized pain medicine. We speculate that the next important step for improving perioperative pain management could be through incorporating these personalized metrics, such as clinical pharmacogenomic testing and patient-reported outcome measurements, into ERAS program.
View details for DOI 10.3390/jcm10122568
View details for PubMedID 34200695
- Destructive procedures of the head and face Deer's Treatment of Pain: An Illustrated Guide for Practitioners 2018
- V2 Rhizotomy Effective Techniques for Managing Trigeminal Neuralgia 2018
Fluoroscopic C-Arm and CT-Guided Selective Radiofrequency Ablation for Trigeminal and Glossopharyngeal Facial Pain Syndromes.
Pain medicine (Malden, Mass.)
Percutaneous radiofrequency ablation (RFA) of the gasserian ganglion through the foramen ovale and the glossopharyngeal nerve at the jugular foramen is a classical approach to treating trigeminal neuralgia (TN) and glossopharyngeal neuralgia (GPN), respectively. However, it can be technically challenging with serious complications. We have thus developed a novel technique utilizing C-arm and computerized tomography (CT) guidance to block TN and GPN. Our goals were to describe a three-dimensional image-based technique to improve patient comfort and to decrease procedural time associated with needle guidance.Consecutive procedures were reviewed. Academic hospital.Three patients with classical TN and GPN and 15 patients with atypical facial pain (AFP) were treated. Numeric rating scale (NRS) scores for pain at pretreatment and at one, three, and 12 months post-treatment were recorded. The primary clinical outcome (50% or more reduction in NRS) and secondary adverse clinical outcome (hematoma, facial numbness, etc.) were monitored. We had a 100% technical success with respect to appropriate needle positioning. All three classical TN/GPN patients had both immediate and sustained pain relief. Complications were minimal. The 15 AFP patients, however, showed more variable results, with only five (33%) having sustained pain relief, while in the other 10 (67%) patients, we observed suboptimal response. We present a novel method and single-center experience with C-arm and CT-guided RFA of facial pain. Quick and accurate needle placement will help future advancements in the RFA algorithm so that more durable and consistent effects can be attained, reducing uncertainty with respect to needle placement as a confounder. The RFA procedure in our study had a satisfying effect for classical TN/GPN patients but was less successful for AFP patients, though it did mirror the results from previous studies.This study is limited by its small sample size and nonrandomized design.
View details for DOI 10.1093/pm/pnx088
View details for PubMedID 28472393
- Pharmacological Management of Chronic Pain Anesthesiology 2017
CT-Guided Percutaneous Infrazygomatic Radiofrequency Neurolysis Through Foramen Rotundum to Treat V2 Trigeminal Neuralgia
2014; 15 (8): 1418-1428
Percutaneous radiofrequency thermocoagulation or neurolysis of Gasserian ganglion through foramen ovale (FO) is the classical approach to treat trigeminal neuralgia (TN). However, it has been technically challenging when individual trigeminal sub-branch nerve block is desired through this approach. We have thus developed a novel computed tomograph-guided technique to block the V2 trigeminal nerve through foramen rotundum (FR). With this technique, we have conducted a study of 27 patients with isolated V2 TN. We hypothesize that this new technique will have comparable clinical outcome with the conventional FO approach.Prospective study.Academic hospitals.Twenty-seven patients with isolated classical V2 TN were enrolled and divided into FO group (N = 12) and FR group (N = 15).Numeric Rating Scale (NRS) scores for facial pain, at pretreatment, immediate postoperative, postoperative 1 day, and 1, 6, and 12 months were recorded. The primary clinical outcome (successful pain relief with 50% or more reduction in NRS) and secondary adverse clinical outcome (hematoma, facial numbness, masticatory weakness, and corneal involvement) were compared and analyzed.Both groups have good immediate and sustained pain relief. However, when compared with the FO group, the FR group is associated with shorter procedural time (29.2 ± 9.3 vs 45.4 ± 22.13 minutes, P < 0.05), has less nonspecific block in V1 and V3 dermatomes, and has fewer adverse outcomes including masticatory weakness (0/15 vs 5/12) and corneal perforation (0/12 vs 1/15).We have developed a novel technique to selectively block the V2 trigeminal nerve at FR. This novel FR approach may be a good alternative to the classical FO approach when an isolated V2 branch block is desired.
View details for DOI 10.1111/pme.12440
View details for Web of Science ID 000342630800025
View details for PubMedID 24716880
Optical control of neuronal excitation and inhibition using a single opsin protein, ChR2.
2013; 3: 3110-?
The effect of electrical stimulation on neuronal membrane potential is frequency dependent. Low frequency electrical stimulation can evoke action potentials, whereas high frequency stimulation can inhibit action potential transmission. Optical stimulation of channelrhodopsin-2 (ChR2) expressed in neuronal membranes can also excite action potentials. However, it is unknown whether optical stimulation of ChR2-expressing neurons produces a transition from excitation to inhibition with increasing light pulse frequencies. Here we report optical inhibition of motor neuron and muscle activity in vivo in the cooled sciatic nerves of Thy1-ChR2-EYFP mice. We also demonstrate all-optical single-wavelength control of neuronal excitation and inhibition without co-expression of inhibitory and excitatory opsins. This all-optical system is free from stimulation-induced electrical artifacts and thus provides a new approach to investigate mechanisms of high frequency inhibition in neuronal circuits in vivo and in vitro.
View details for DOI 10.1038/srep03110
View details for PubMedID 24173561
View details for PubMedCentralID PMC3813941
- Treatment efficacy and technical advantages of ipsilateral temporary spinal nerve root stimulation for unilateral postherpetic neuralgia Society for Neuroscience 2021 Annual Meeting 2021
Intravenous Ketamine as an Adjunct for Pachyonychia Congenita-Associated Pain: A Case Report.
Pachyonychia congenita (PC) is a rare, inherited disorder of keratin filaments characterized by palmoplantar hyperkeratosis, keratoderma, and extreme pain. Management is largely symptomatic and typically involves multimodal pain control strategies. Here, we report the treatment of one 21-year-old man's refractory neuropathic PC pain with a 4-day inpatient ketamine infusion. Within 1 night of beginning treatment, his pain diminished to a 0/10 without any adverse effects, with effects lasting 2 weeks. No reported PC pain regimens have made use of intravenous ketamine; thus, we suggest recurrent ketamine infusions as an additional option in the multimodal pain regimen for patients with PC.
View details for DOI 10.1213/XAA.0000000000001066
View details for PubMedID 31343433
- Short-term ketamine infusion for acute pain flare in a patient with calciphylaxis The 54th Western Anesthesia Residents Conference (WARC) Annual Meeting 2016
- Ketamine Infusion: A Useful Tool for Chronic Neuropathic Pain AAPM American Academy of Pain Medicine Annual Meeting. 2016
- Flat panel c-arm and ct-guided selective trigeminal and glossopharyngeal radiofrequency rhizotomy for facial pain syndromes: a step-by-step case-based instruction and multidisciplinary single center experience Journal of NeuroInterventional Surgery 2015
A Retrospective Study of Chronic Post-Surgical Pain following Thoracic Surgery: Prevalence, Risk Factors, Incidence of Neuropathic Component, and Impact on Qualify of Life.
2014; 9 (2)
Thoracic surgeries including thoracotomy and VATS are some of the highest risk procedures that often lead to CPSP, with or without a neuropathic component. This retrospective study aims to determine retrospectively the prevalence of CPSP following thoracic surgery, its predicting risk factors, the incidence of neuropathic component, and its impact on quality of life.Patients who underwent thoracic surgeries including thoracotomy and VATS between 01/2010 and 12/2011 at the First Affiliated Hospital, School of Medicine, Zhejiang University were first contacted and screened for CPSP following thoracic surgery via phone interview. Patients who developed CPSP were then mailed with a battery of questionnaires, including a questionnaire referenced to Maguire's research, a validated Chinese version of the ID pain questionnaire, and a SF-36 Health Survey. Logistic regression analyses were subsequently performed to identify risk factors for CPSP following thoracic surgery and its neuropathic component.The point prevalence of CPSP following thoracic surgery was 24.9% (320/1284 patients), and the point prevalence of neuropathic component of CPSP was 32.5% (86/265 patients). CPSP following thoracic surgery did not improve significantly with time. Multiple predictive factors were identified for CPSP following thoracic surgery, including age<60 years old, female gender, prolonged duration of post-operative chest tube drainage (≥4 days), options of post-operative pain management, and pre-existing hypertension. Furthermore, patients who experienced CPSP following thoracic surgery were found to have significantly decreased physical function and worse quality of life, especially those with neuropathic component.Our study demonstrated that nearly 1 out of 4 patients underwent thoracic surgery might develop CPSP, and one third of them accompanied with a neuropathic component. Early prevention as well as aggressive treatment is important for patients with CPSP following thoracic surgery to achieve a high quality of life.
View details for DOI 10.1371/journal.pone.0090014
View details for PubMedID 24587187
View details for PubMedCentralID PMC3938555
- Optogenetic modulation of nociceptive C-fibers. The 50th Western Anesthesia Residents Conference The 50th Western Anesthesia Residents Conference (WARC) Annual Meeting 2012
- Deep Vein Thrombosis and Pulmonary Embolism Manual of Clinical Anesthesiology 2011; 470-475
- Low-dose spinal anesthesia for an elderly woman with severe Hypertrophic Obstructive Cardiomyopathy (HOCM) and several co-morbidities for an urgent orthopedic procedure American Society of Anesthesiologists Annual Meeting 2010
G protein-activated inwardly rectifying potassium channels mediate depotentiation of long-term potentiation
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
2009; 106 (2): 635-640
Excitatory synapses in the brain undergo activity-dependent changes in the strength of synaptic transmission. Such synaptic plasticity as exemplified by long-term potentiation (LTP) is considered a cellular correlate of learning and memory. The presence of G protein-activated inwardly rectifying K(+) (GIRK) channels near excitatory synapses on dendritic spines suggests their possible involvement in synaptic plasticity. However, whether activity-dependent regulation of GIRK channels affects excitatory synaptic plasticity is unknown. In a companion article we have reported activity-dependent regulation of GIRK channel density in cultured hippocampal neurons that requires activity of NMDA receptors (NMDAR) and protein phosphatase-1 (PP1) and takes place within 15 min. In this study, we performed whole-cell recordings of cultured hippocampal neurons and found that NMDAR activation increases basal GIRK current and GIRK channel activation mediated by adenosine A(1) receptors, but not GABA(B) receptors. Given the similar involvement of NMDARs, adenosine A(1) receptors, and PP1 in depotentiation of LTP caused by low-frequency stimulation that immediately follows LTP-inducing high-frequency stimulation, we wondered whether NMDAR-induced increase in GIRK channel surface density and current may contribute to the molecular mechanisms underlying this specific depotentiation. Remarkably, GIRK2 null mutation or GIRK channel blockade abolishes depotentiation of LTP, demonstrating that GIRK channels are critical for depotentiation, one form of excitatory synaptic plasticity.
View details for DOI 10.1073/pnas.0811685106
View details for Web of Science ID 000262804000051
View details for PubMedID 19118199
Neuronal activity regulates phosphorylation-dependent surface delivery of G protein-activated inwardly rectifying potassium channels
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
2009; 106 (2): 629-634
G protein-activated inwardly rectifying K(+) (GIRK) channels regulate neuronal excitability by mediating inhibitory effects of G protein-coupled receptors for neurotransmitters and neuromodulators. Notwithstanding many studies reporting modulation of GIRK channel function, whether neuronal activity regulates GIRK channel trafficking remains an open question. Here we report that NMDA receptor activation in cultured dissociated hippocampal neurons elevates surface expression of the GIRK channel subunits GIRK1 and GIRK2 in the soma, dendrites, and dendritic spines within 15 min. This activity-induced increase in GIRK surface expression requires protein phosphatase-1-mediated dephosphorylation of a serine residue (Ser-9) preceding the GIRK2 Val-13/Leu-14 (VL) internalization motif, thereby promoting channel recycling. Because activation of GIRK channels hyperpolarizes neuronal membranes, the NMDA receptor-induced regulation of GIRK channel trafficking may represent a dynamic adjustment of neuronal excitability in response to inhibitory neurotransmitters and/or neuromodulators.
View details for DOI 10.1073/pnas.0811615106
View details for Web of Science ID 000262804000050
View details for PubMedID 19118198
SK channels mediate NADPH oxidase-independent reactive oxygen species production and apoptosis in granulocytes
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
2006; 103 (46): 17548-17553
Neutrophils are immune cells that bind to, engulf, and destroy bacterial and fungal pathogens in infected tissue, and their clearance by apoptosis is essential for the resolution of inflammation. Killing involves both oxidative and nonoxidative processes, the oxidative pathway requiring electrogenic production of superoxide by the membrane-bound NADPH oxidase complex. A variety of stimuli, from bacterial chemotactic peptides to complement- or IgG-opsonized microbes, can induce the production of reactive oxygen species (ROS) by neutrophils, presumably by means of NADPH oxidase. We report here that 1-ethyl-2-benzimidazolinone (1-EBIO), an activator of Ca2+-activated potassium channels of small conductance (SK) and intermediate conductance (IK), causes production of superoxide and hydrogen peroxide by neutrophils and granulocyte-differentiated PLB-985 cells. This response can be partially inhibited by the SK blocker apamin, which inhibits a Ca2+-activated K+ current in these cells. Analysis of RNA transcripts indicates that channels encoded by the SK3 gene carry this current. The effects of 1-EBIO and apamin are independent of the NADPH oxidase pathway, as demonstrated by using a PLB-985 cell line lacking the gp91phox subunit. Rather, 1-EBIO and apamin modulate mitochondrial ROS production. Consistent with the enhanced ROS production and K+ efflux mediated by 1-EBIO, we found that this SK opener increased apoptosis of PLB-985 cells. Together, these findings suggest a previously uncharacterized mechanism for the regulation of neutrophil ROS production and programmed cell death.
View details for DOI 10.1073/pnas.0607914103
View details for Web of Science ID 000242249400086
View details for PubMedID 17085590
Intra- and intersubunit cooperativity in activation of BK channels by Ca2+ (vol 128, pg 389, 2006)
JOURNAL OF GENERAL PHYSIOLOGY
2006; 128 (5): 629-629
View details for Web of Science ID 000241670600014
K+ channel selectivity depends on kinetic as well as thermodynamic factors
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
2006; 103 (39): 14361-14366
Potassium channels are necessary for a number of essential biological tasks such as the generation of action potentials and setting the resting membrane potential in cells, both of which require that these channels selectively permit the passage of potassium ions while suppressing the flow of other ions. Generally, this selectivity is attributed to a narrow stretch of the channel known as the selectivity filter. Over this stretch ions are dehydrated, and the backbone oxygen atoms of the protein mimic the ion's loss of coordination by water. However, channels are long pores with spatially distinct ion-binding sites that all must be traversed during ion permeation. We have shown that selectivity of mutant Kir3.2 (GIRK2) channels can be substantially amplified by introducing acidic residues into the cavity, a binding site below the selectivity filter. Here, we carry out electrostatic calculations on homology models to quantify the degree of stabilization that these mutations have on ions in the cavity. We then construct a multiion model of ion permeation to calculate the channel's permeability to potassium relative to sodium. This kinetic model uses rates derived from the electrostatic calculations and demonstrates that nonselective electrostatic stabilization of cations in the cavity can amplify channel selectivity independently of the selectivity filter. This nonintuitive result highlights the dependence of channel properties on the entire channel architecture and suggests that selectivity may not be fully understood by focusing solely on thermodynamic considerations of ion dehydration and the energetics of the selectivity filter.
View details for DOI 10.1073/pnas.0606662103
View details for Web of Science ID 000240968100021
View details for PubMedID 16983068
Modulation of basal and receptor-induced GIRK potassium channel activity and neuronal excitability by the mammalian PINS homolog LGN
2006; 50 (4): 561-573
G protein-activated inwardly rectifying potassium (GIRK) channels mediate slow synaptic inhibition and control neuronal excitability. It is unknown whether GIRK channels are subject to regulation by guanine dissociation inhibitor (GDI) proteins like LGN, a mammalian homolog of Drosophila Partner of Inscuteable (mPINS). Here we report that LGN increases basal GIRK current but reduces GIRK activation by metabotropic transmitter receptors coupled to Gi or Go, but not Gs. Moreover, expression of its N-terminal, TPR-containing protein interaction domains mimics the effects of LGN in mammalian cells, probably by releasing sequestered endogenous LGN. In hippocampal neurons, expression of LGN, or LGN fragments that mimic or enhance LGN activity, hyperpolarizes the resting potential due to increased basal GIRK activity and reduces excitability. Using Lenti virus for LGN RNAi to reduce endogenous LGN levels in hippocampal neurons, we further show an essential role of LGN for maintaining basal GIRK channel activity and for harnessing neuronal excitability.
View details for DOI 10.1016/j.neuron.2006.03.046
View details for Web of Science ID 000237875200008
View details for PubMedID 16701207
- Linker-gating ring complex as passive spring and Ca2+-dependent machine for a voltage-and Ca2+-activated potassium channel (vol 42, pg 745, 2004) NEURON 2005; 45 (4): 637-637
- Both intra- and inter-subunit cooperativity contribute to the activation of BK channels by calcium 2005
- Sodium-activated K+ channels are also calcium-activated K+ channels 2004
- Mechanism for mechanical coupling between the gate and the gating ring in BK channels 2004
beta 1 subunits facilitate gating of BK channels by acting through the Ca2+, but not the Mg2+, activiating mechanisms
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
2003; 100 (17): 10061-10066
The beta1 subunit of BK (large conductance Ca2+ and voltage-activated K+) channels is essential for many key physiological processes, such as controlling the contraction of smooth muscle and the tuning of hair cells in the cochlea. Although it is known that the beta1 subunit greatly increases the open probability of BK channels, little is known about its mechanism of action. We now explore this mechanism by using channels in which the Ca2+- and Mg2+-dependent activating mechanisms have been disrupted by mutating three sites to remove the Ca2+ and Mg2+ sensitivity. We find that the presence of the beta1 subunit partially restores Ca2+ sensitivity to the triply mutated channels, but not the Mg2+ sensitivity. We also find that the beta1 subunit has no effect on the Mg2+ sensitivity of WT BK channels, in contrast to its pronounced effect of increasing the apparent Ca2+ sensitivity. These observations suggest that the beta1 subunit increases open probability by working through the Ca2+-dependent, rather than Mg2+-dependent, activating mechanisms, and that the action of the beta1 subunit is not directly on the Ca2+ binding sites, but on the allosteric machinery coupling the sites to the gate. The differential effects of the beta1 subunit on the Ca2+ and Mg2+ activation of the channel suggest that these processes act separately. Finally, we show that Mgi2+ inhibits, rather than activates, BK channels in the presence of the beta1 subunit for intermediate levels of Cai2+. This Mg2+ inhibition in the presence of the beta1 subunit provides an additional regulatory mechanism of BK channel activity.
View details for DOI 10.1073/pnas.1731650100
View details for Web of Science ID 000184926000079
View details for PubMedID 12893878
Slo1 tail domains, but not the Ca2+ bowl, are required for the beta 1 subunit to increase the apparent Ca2+ sensitivity of BK channels
JOURNAL OF GENERAL PHYSIOLOGY
2002; 120 (6): 829-843
Functional large-conductance Ca(2+)- and voltage-activated K(+) (BK) channels can be assembled from four alpha subunits (Slo1) alone, or together with four auxiliary beta1 subunits to greatly increase the apparent Ca(2+) sensitivity of the channel. We examined the structural features involved in this modulation with two types of experiments. In the first, the tail domain of the alpha subunit, which includes the RCK2 (regulator of K(+) conductance) domain and Ca(2+) bowl, was replaced with the tail domain of Slo3, a BK-related channel that lacks both a Ca(2+) bowl and high affinity Ca(2+) sensitivity. In the second, the Ca(2+) bowl was disrupted by mutations that greatly reduce the apparent Ca(2+) sensitivity. We found that the beta1 subunit increased the apparent Ca(2+) sensitivity of Slo1 channels, independently of whether the alpha subunits were expressed as separate cores (S0-S8) and tails (S9-S10) or full length, and this increase was still observed after the Ca(2+) bowl was mutated. In contrast, beta1 subunits no longer increased Ca(2+) sensitivity when Slo1 tails were replaced by Slo3 tails. The beta1 subunits were still functionally coupled to channels with Slo3 tails, as DHS-I and 17 beta-estradiol activated these channels in the presence of beta1 subunits, but not in their absence. These findings indicate that the increase in apparent Ca(2+) sensitivity induced by the beta1 subunit does not require either the Ca(2+) bowl or the linker between the RCK1 and RCK2 domains, and that Slo3 tails cannot substitute for Slo1 tails. The beta1 subunit also induced a decrease in voltage sensitivity that occurred with either Slo1 or Slo3 tails. In contrast, the beta1 subunit-induced increase in apparent Ca(2+) sensitivity required Slo1 tails. This suggests that the allosteric activation pathways for these two types of actions of the beta1 subunit may be different.
View details for DOI 10.1085/jgp.20028692
View details for Web of Science ID 000179670000009
View details for PubMedID 12451052
Role of fragile X mental retardation protein in chronic pain.
; 16: 1744806920928619
Chronic pain has detrimental effects on one's quality of life. However, its treatment options are very limited, and its underlying pathogenesis remains unclear. Recent research has suggested that fragile X mental retardation protein is involved in the development of chronic pain, making it a potential target for prevention and treatment. The current review of literature will examine the function of fragile X mental retardation protein and its associated pathways, through which we hope to gain insight into how fragile X mental retardation protein may contribute to nociceptive sensitization and chronic pain.
View details for DOI 10.1177/1744806920928619
View details for PubMedID 32496847