Non-canonical molecular targets for novel analgesics: Intracellular calcium and HCN channels

2021 ◽  
Vol 19 ◽  
Author(s):  
Daniel C. Cook ◽  
Peter A. Goldstein
Keyword(s):  
Ion Channels ◽  
Intracellular Calcium ◽  
Ryanodine Receptors ◽  
Healthcare Providers ◽  
Opioid Analgesics ◽  
Hcn Channels ◽  
Pain Medications ◽  
Suitable Target ◽  
Μ Opioid Receptor ◽  
Sensory Nervous System

Pain is a prevalent biopsychosocial condition that poses a significant challenge to healthcare providers, contributes substantially to disability, and is a major economic burden worldwide. An overreliance on opioid analgesics, which primarily target the μ-opioid receptor, has caused devastating morbidity and mortality in the form of misuse and overdose-related death. Thus, novel analgesic medications are needed that can effectively treat pain and provide an alternative to opioids. A variety of cellular ion channels contribute to nociception, the response of the sensory nervous system to a noxious stimulus that commonly leads to pain. Ion channels involved in nociception may provide a suitable target for pharmacologic modulation to achieve pain relief. This narrative review summarizes the evidence for two ion channels that merit consideration as targets for non-opioid pain medications: ryanodine receptors (RyRs), which are intracellular calcium channels, and hyperpolarization-activated cyclic nucleotide-gated (HCN) channels, which belong the superfamily of voltage-gated K+ channels. The role of these channels in nociception and neuropathic pain is discussed and suitability as targets for novel analgesics and antihyperalgesics is considered.

Control of secretion in anterior pituitary cells--linking ion channels, messengers and exocytosis

1988 ◽  
Vol 139 (1) ◽  
pp. 287-316
Author(s):  
W. T. Mason ◽  
S. R. Rawlings ◽  
P. Cobbett ◽  
S. K. Sikdar ◽  
R. Zorec ◽  
...  
Keyword(s):  
Ion Channels ◽  
Intracellular Calcium ◽  
Anterior Pituitary ◽  
Hormone Secretion ◽  
Cell Types ◽  
Pituitary Cell ◽  
Pituitary Cells ◽  
Calcium Activity ◽  
Anterior Pituitary Cells ◽  
Voltage Dependent

Normal anterior pituitary cells, in their diversity and heterogeneity, provide a rich source of models for secretory function. However, until recently they have largely been neglected in favour of neoplastic, clonal tumour cell lines of pituitary origin, which have enabled a number of studies on supposedly homogeneous cell types. Because many of these lines appear to lack key peptide and neurotransmitter receptors, as well as being degranulated with accompanying abnormal levels of secretion, we have developed a range of normal primary anterior pituitary cell cultures using dispersion and enrichment techniques. By studying lactotrophs, somatotrophs and gonadotrophs we have revealed a number of possible transduction mechanisms by which receptors for hypothalamic peptides and neurotransmitters may control secretion. In particular, the transduction events controlling secretion from pituitary cells may differ fundamentally from those found in other cell types. Patch-clamp recordings in these various pituitary cell preparations have revealed substantial populations of voltage-dependent Na+, Ca2+ and K+ channels which may support action potentials in these cells. Although activation of these channels may gate Ca2+ entry to the cells under some conditions, our evidence taken with that of other laboratories suggests that peptide-receptor interactions leading to hormone secretion occur independently of significant membrane depolarization. Rather, secretion of hormone and rises in intracellular calcium measured with new probes for intracellular calcium activity, can occur in response to hypothalamic peptide activation in the absence of substantial changes in membrane potential. These changes in intracellular calcium activity almost certainly depend on both intracellular and extracellular calcium sources. In addition, strong evidence of a role for multiple intracellular receptors and modulators in the secretory event suggests we should consider the plasma membrane channels important for regulation of hormone secretion to be predominantly agonist-activated, rather than of the more conventional voltage-dependent type. Likewise, evidence from new methods for recording single ion channels suggests the existence of intracellular sites for channel modulation, implying they too may play an important role in secretory regulation. We shall consider new data and new technology which we hope will provide key answers to the many intriguing questions surrounding the control of pituitary hormone secretion. We shall highlight our work with recordings of single ion channels activated by peptides, and recent experiments using imaging of intracellular ionized free calcium.(ABSTRACT TRUNCATED AT 250 WORDS)

Mechanisms and Physiological Implications of Cooperative Gating of Ion Channels Clusters

2021 ◽  
Author(s):  
Rose Ellen Dixon ◽  
Manuel F. Navedo ◽  
Marc D Binder ◽  
L. Fernando Santana
Keyword(s):  
Ion Channels ◽  
Action Potential ◽  
Transient Receptor Potential ◽  
Imaging Techniques ◽  
Ryanodine Receptors ◽  
Receptor Potential ◽  
Transient Receptor Potential Channels ◽  
Cardiac Cells ◽  
Fine Tuning ◽  
Voltage Gated

Ion channels play a central role in the regulation of nearly every cellular process. Dating back to the classic 1952 Hodgkin-Huxley model of the generation of the action potential, ion channels have always been thought of as independent agents. A myriad of recent experimental findings exploiting advances in electrophysiology, structural biology, and imaging techniques, however, have posed a serious challenge to this long-held axiom as several classes of ion channels appear to open and close in a coordinated, cooperative manner. Ion channel cooperativity ranges from variable-sized oligomeric cooperative gating in voltage-gated, dihydropyridine-sensitive Cav1.2 and Cav1.3 channels to obligatory dimeric assembly and gating of voltage-gated Nav1.5 channels. Potassium channels, transient receptor potential channels, hyperpolarization cyclic nucleotide-activated channels, ryanodine receptors (RyRs), and inositol trisphosphate receptors (IP3Rs) have also been shown to gate cooperatively. The implications of cooperative gating of these ion channels range from fine tuning excitation-contraction coupling in muscle cells to regulating cardiac function and vascular tone, to modulation of action potential and conduction velocity in neurons and cardiac cells, and to control of pace-making activity in the heart. In this review, we discuss the mechanisms leading to cooperative gating of ion channels, their physiological consequences and how alterations in cooperative gating of ion channels may induce a range of clinically significant pathologies.

Distinct Intracellular Calcium Profiles Following Influx Through N- Versus L-Type Calcium Channels: Role of Ca2+-Induced Ca2+ Release

2004 ◽  
Vol 92 (1) ◽  
pp. 135-143 ◽  
Author(s):  
Keith Tully ◽  
Steven N. Treistman
Keyword(s):  
Intracellular Calcium ◽  
Ryanodine Receptors ◽  
Decay Rates ◽  
Selective Activation ◽  
Intracellular Ca ◽  
Pheochromocytoma Pc12 ◽  
High Concentrations ◽  
Neuronal Functions ◽  
Temporal Profiles

Selective activation of neuronal functions by Ca2+ is determined by the kinetic profile of the intracellular calcium ([Ca2+]i) signal in addition to its amplitude. Concurrent electrophysiology and ratiometric calcium imaging were used to measure transmembrane Ca2+ current and the resulting rise and decay of [Ca2+]i in differentiated pheochromocytoma (PC12) cells. We show that equal amounts of Ca2+ entering through N-type and L-type voltage-gated Ca2+ channels result in significantly different [Ca2+]i temporal profiles. When the contribution of N-type channels was reduced by ω-conotoxin MVIIA treatment, a faster [Ca2+]i decay was observed. Conversely, when the contribution of L-type channels was reduced by nifedipine treatment, [Ca2+]i decay was slower. Potentiating L-type current with BayK8644, or inactivating N-type channels by shifting the holding potential to −40 mV, both resulted in a more rapid decay of [Ca2+]i. Channel-specific differences in [Ca2+]i decay rates were abolished by depleting intracellular Ca2+ stores with thapsigargin or by blocking ryanodine receptors with ryanodine, suggesting the involvement of Ca2+-induced Ca2+ release (CICR). Further support for involvement of CICR is provided by the demonstration that caffeine slowed [Ca2+]i decay while ryanodine at high concentrations increased the rate of [Ca2+]i decay. We conclude that Ca2+ entering through N-type channels is amplified by ryanodine receptor mediated CICR. Channel-specific activation of CICR provides a mechanism whereby the kinetics of intracellular Ca2+ leaves a fingerprint of the route of entry, potentially encoding the selective activation of a subset of Ca2+-sensitive processes within the neuron.

Inappropriate opioid prescribing practices: A narrative review

2019 ◽  
Vol 76 (16) ◽  
pp. 1231-1237 ◽  
Author(s):  
Brian Kim ◽  
Seonaid Nolan ◽  
Tara Beaulieu ◽  
Stephen Shalansky ◽  
Lianping Ti
Keyword(s):  
Literature Review ◽  
Data Extraction ◽  
Inappropriate Prescribing ◽  
Healthcare Providers ◽  
Opioid Analgesics ◽  
Drug Misuse ◽  
Patient Specific ◽  
Prescribing Practices ◽  
Prescription Drug Misuse ◽  
Opioid Prescribing

Abstract Purpose Results of a literature review to identify indicators of inappropriate opioid prescribing are presented. Summary While prescription opioids can be effective for the treatment of acute pain, inappropriate prescribing practices can increase the risk of opioid-related harms, including overdose and mortality. To date, little research has been conducted to determine how best to define inappropriate opioid prescribing. Five electronic databases were searched to identify studies (published from database inception to January 2017) that defined inappropriate opioid prescribing practices. Search terms varied slightly across databases but included opioid, analgesics, inappropriate prescribing, practice patterns, and prescription drug misuse. Gray literature and references of published literature reviews were manually searched to identify additional relevant articles. From among the 4,665 identified articles, 41 studies were selected for data extraction and analysis. Fourteen studies identified high-daily-dose opioid prescriptions, 14 studies identified coadministration of benzodiazepines and opioids, 10 studies identified inappropriate opioid prescribing in geriatric populations, 8 studies identified other patient-specific factors, 4 studies identified opioid prescribing for the wrong indication, and 4 studies identified factors such as initiation of long-acting opioids in opioid-naive patients as indicators of inappropriate opioid prescribing. Conclusion A literature review identified various indicators of inappropriate opioid prescribing, including the prescribing of high daily doses of opioids, concurrent benzodiazepine administration, and geriatric-related indicators. Given the significant contribution of inappropriate opioid prescribing to opioid-related harms, identification of these criteria is important to inform and improve opioid prescribing practices among healthcare providers.

scholarly journals Phosphorylation-Dependent Regulation of Ryanodine Receptors

2001 ◽  
Vol 153 (4) ◽  
pp. 699-708 ◽  
Author(s):  
Steven O. Marx ◽  
Steven Reiken ◽  
Yuji Hisamatsu ◽  
Marta Gaburjakova ◽  
Jana Gaburjakova ◽  
...  
Keyword(s):  
Ion Channels ◽  
Ion Channel ◽  
Calcium Release ◽  
Ryanodine Receptors ◽  
Rapid Identification ◽  
Calcium Release Channels ◽  
Macromolecular Complexes ◽  
Protein Binding Sites ◽  
Skeletal Muscle Contraction

Ryanodine receptors (RyRs), intracellular calcium release channels required for cardiac and skeletal muscle contraction, are macromolecular complexes that include kinases and phosphatases. Phosphorylation/dephosphorylation plays a key role in regulating the function of many ion channels, including RyRs. However, the mechanism by which kinases and phosphatases are targeted to ion channels is not well understood. We have identified a novel mechanism involved in the formation of ion channel macromolecular complexes: kinase and phosphatase targeting proteins binding to ion channels via leucine/isoleucine zipper (LZ) motifs. Activation of kinases and phosphatases bound to RyR2 via LZs regulates phosphorylation of the channel, and disruption of kinase binding via LZ motifs prevents phosphorylation of RyR2. Elucidation of this new role for LZs in ion channel macromolecular complexes now permits: (a) rapid mapping of kinase and phosphatase targeting protein binding sites on ion channels; (b) predicting which kinases and phosphatases are likely to regulate a given ion channel; (c) rapid identification of novel kinase and phosphatase targeting proteins; and (d) tools for dissecting the role of kinases and phosphatases as modulators of ion channel function.

Opioid use in the acute setting: A survey of providers at an academic medical center

2018 ◽  
Vol 14 (3) ◽  
pp. 203-210 ◽  
Author(s):  
Douglas R. Oyler, PharmD ◽  
Kristy S. Deep, MD ◽  
Phillip K. Chang, MD
Keyword(s):  
Medical Center ◽  
Academic Medical Center ◽  
Healthcare Providers ◽  
High Risk Patient ◽  
Opioid Analgesics ◽  
Opioid Use ◽  
Cross Sectional ◽  
Academic Medical ◽  
Clinical Scenarios ◽  
Nonopioid Analgesics

Objective: To examine attitudes, beliefs, and influencing factors of inpatient healthcare providers regarding prescription of opioid analgesics.Design: Electronic cross-sectional survey.Setting: Academic medical center.Participants: Physicians, advanced practice providers, and pharmacists from a single academic medical center in the southeast United States.Main Outcome Measures: Respondents completed survey items addressing: (1) their practice demographics, (2) their opinions regarding overall use, safety, and efficacy of opioids compared to other analgesics, (3) specific clinical scenarios, (4) main pressures to prescribe opioids, and (5) confidence/comfort prescribing opioids or nonopioids in select situations.Results: The majority of the sample (n = 363) were physicians (60.4 percent), with 69.4 percent of physicians being attendings. Most respondents believed that opioids were overused at our institution (61.7 percent); nearly half thought opioids had similar efficacy to other analgesics (44.1 percent), and almost all believed opioids were more dangerous than other analgesics (88.1 percent). Many respondents indicated that they would modify a chronic regimen for a high-risk patient, and use of nonopioids in specific scenarios was high. However, this use was often in combination with opioids. Respondents identified patients (64 percent) and staff (43.1 percent) as the most significant sources of pressure to prescribe opioids during an admission; the most common sources of pressure to prescribe opioidson discharge were to facilitate discharge (44.8 percent) and to reduce follow-up requests, calls, or visits (36.3 percent). Resident physicians appear to experience more pressure to prescribe opioids than other providers. Managing pain in patients with substance use disorders and effectively using nonopioid analgesics were the most common educational needs identified by respondents.Conclusion: Most individuals believe opioid analgesics are overused in our specific setting, commonly to satisfy patient requests. In general, providers feel uncomfortable prescribing nonopioid analgesics to patients.

An Internet-based survey evaluating attitudes of cancer patients towards pain intervention

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 18540-18540
Author(s):  
C. B. Simone ◽  
N. Vapiwala ◽  
M. K. Hampshire ◽  
J. M. Metz
Keyword(s):  
Cancer Treatment ◽  
Cancer Patients ◽  
Pain Control ◽  
Statistical Significance ◽  
Healthcare Providers ◽  
Common Symptom ◽  
Pain Medications ◽  
Education Levels ◽  
Pain Intervention ◽  
Pain Symptoms

18540 Background: Pain is a common symptom among cancer patients (pts), but many pts experience inadequate medical management for pain. There are little data quantifying reasons that cancer pts fail to receive optimal analgesic treatment. This study evaluated those reasons and investigated the causes of pain in cancer pts. Methods: An Internet-based questionnaire assessing pt demographics and pain symptoms was piloted with pts and healthcare providers and posted on the OncoLink (http://www.oncolink.org) website. The questionnaire included 22 queries evaluating medication utilization, pain control and attitudes regarding pain medications. The questionnaire was IRB approved and held on a secure server. Between 11/05–1/06, 99 pts responded to the questionnaire. They were predominantly Caucasian (76%), female (78%) and pursued education beyond high school (66%). The most common diseases included cancer of the breast (51%), lung (8%) and brain (6%). Cancer treatment included surgery (75%), chemotherapy (63%) and radiation (45%). Results: Half (49%) of the respondents reported pain directly from their cancer and 42% complained of pain due to cancer treatment. This pain was primarily intermittent (42%) or chronic (35%). Most (77%) pts did not use medication specifically to help manage their pain. Analgesic usage trended less in women (19% vs. 36%, p = 0.10), Caucasians (19% vs. 38%, p = 0.06), and pts with higher education levels (17% vs. 26%, p = 0.29) but did not reach statistical significance. Reasons most commonly cited for not taking analgesics included the healthcare provider not recommending medications (86%), fear of becoming addicted or dependent (80%) and an inability to pay for medication (75%). Participants experiencing pain, but not taking analgesics, sought alternative measures for pain control such as physical therapy (84%), massage (7%) and acupuncture (4%). Conclusions: Although many cancer pts experience pain regularly, both from their cancer and cancer treatment, most pts in this study did not seek out analgesics. Pts do seek complementary therapies for pain control. Healthcare providers should regularly have open discussions with pts regarding pain symptoms. Further study will be needed to evaluate attitudes of pts towards pain based on disease condition. No significant financial relationships to disclose.

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