Pharmacy and Pharmaceutical Sciences Commons^™

[(Wr)8Wkβa]-Doxorubicin Conjugate: A Delivery System To Overcome Multi-Drug Resistance Against Doxorubicin, Khalid Zoghebi, Hamidreza Montazeri Aliabadi, Rakesh Kumar Tiwari, Keykavous Parang

Pharmacy Faculty Articles and Research

Doxorubicin (Dox) is an anthracycline chemotherapeutic agent used to treat breast, leukemia, and lymphoma malignancies. However, cardiotoxicity and inherent acquired resistance are major drawbacks, limiting its clinical application. We have previously shown that cyclic peptide [WR]₉ containing alternate tryptophan (W) and arginine (R) residues acts as an efficient molecular transporter. An amphiphilic cyclic peptide containing a lysine (K) residue and alternative W and R was conjugated through a free side chain amino group with Dox via a glutarate linker to afford [(WR)₈WKβA]-Dox conjugate. Antiproliferative assays were performed in different cancer cell lines using the conjugate and the …

A Global Review On Short Peptides: Frontiers And Perspectives, Vasso Apostolopoulos, Joanna Bojarska, Tsun-Thai Chai, Sherif Elnagdy, Krzysztof Kaczmarek, John Matsoukas, Roger New, Keykavous Parang, Octavio Paredes Lopez, Hamideh Parhiz, Conrad O. Perera, Monica Pickholz, Milan Remko, Michele Saviano, Mariusz Skwarczynski, Yefeng Tang, Wojciech M. Wolf, Taku Yoshiya, Janusz Zabrocki, Piotr Zielenkiewicz, Maha Alkhazindar, Vanessa Barriga, Konstantinos Kelaidonis, Elham Mousavinezhad Sarasia, Istvan Toth

Pharmacy Faculty Articles and Research

Peptides are fragments of proteins that carry out biological functions. They act as signaling entities via all domains of life and interfere with protein-protein interactions, which are indispensable in bio-processes. Short peptides include fundamental molecular information for a prelude to the symphony of life. They have aroused considerable interest due to their unique features and great promise in innovative bio-therapies. This work focusing on the current state-of-the-art short peptide-based therapeutical developments is the first global review written by researchers from all continents, as a celebration of 100 years of peptide therapeutics since the commencement of insulin therapy in the 1920s. …

Pharmacist-Led Programs To Increase Statin Prescribing: A Narrative Review Of The Literature, Mary Elkomos, Raha Jahromi, Michael S. Kelly

Pharmacy Faculty Articles and Research

Statins are lipid-lowing medications shown to reduce cardiovascular events and are recommended for specific patient populations at elevated risk of atherosclerotic cardiovascular disease (ASCVD). Despite the demonstrated efficacy of statins for reducing ASCVD risk, and guidance on which populations should receive statin therapy, a substantial portion of eligible patients are not prescribed statin therapy. Pharmacists have attempted to increase the number of eligible patients receiving appropriate statin therapy through a variety of interventions and across several clinical settings. In this article, we highlight multiple studies evaluating the effectiveness of pharmacist-led interventions to improve statin use. A total of seven studies …

Differential Modulation Of Sk Channel Subtypes By Phosphorylation, Young-Woo Nam, Dezhi Kong, Dong Wang, Razan Orfali, Rinzhin T. Sherpa, Jennifer Totonchy, Surya M. Nauli, Miao Zhang

Pharmacy Faculty Articles and Research

Small-conductance Ca²⁺-activated K⁺ (SK) channels are voltage-independent and are activated by Ca²⁺ binding to the calmodulin constitutively associated with the channels. Both the pore-forming subunits and the associated calmodulin are subject to phosphorylation. Here, we investigated the modulation of different SK channel subtypes by phosphorylation, using the cultured endothelial cells as a tool. We report that casein kinase 2 (CK2) negatively modulates the apparent Ca²⁺ sensitivity of SK1 and IK channel subtypes by more than 5-fold, whereas the apparent Ca²⁺ sensitivity of the SK3 and SK2 subtypes is only reduced by ∼2-fold, when heterologously …

Structural Characterization And In Vitro Antiproliferative Activity Of Non-Specific Lipid Transfer Protein 1 (Nsltp1) From Fennel (Foeniculum Vulgare) Seeds, Mekdes Megeressa

Pharmaceutical Sciences (PhD) Dissertations

Non-specific lipid transfer proteins (nsLTPs) are cationic proteins involved in intracellular lipid shuttling, in growth and reproduction, as well as in defense against pathogenic microbes. Even though the primary and spatial structures of some nsLTPs from different plants indicate their similar features, they exhibit distinct lipid-binding specificities signifying their various biological roles that dictate further structural study. The present study determined the complete amino acid sequence, in silico 3D structure modeling, and in vitro antiproliferative activity of nsLTP1 from fennel (Foeniculum vulgare) seeds.

Fennel is a member of the family Umbelliferae (Apiaceae) native to southern Europe and the …

Equity For All: Providing Accessible Healthcare For Patients Living With Disabilities, Michelle L. Blakely, Sharon E. Connor, Jennifer Ko

Pharmacy Faculty Books and Book Chapters

At the end of this activity, students will be able to:

• Identify relevant resources to assist patients living with disabilities
• Recommend appropriate patient-specific resources to minimize barriers to health
• Identify strategies to enhance the healthcare experience of patients living with disabilities
• Describe the policies that currently exist to enhance care for patients living with disabilities

Let Your Pharmacist Be Your Guide: Navigating Barriers To Pharmaceutical Access, Jennifer Ko, Miranda Steinkopf, Sharon E. Connor

Pharmacy Faculty Books and Book Chapters

At the end of this case, students will be able to: • Describe policy, organizational, and individual factors that contribute to barriers to accessing medications and pharmaceutical care • Identify resources to improve access to affordable medications for uninsured and underinsured patients • Recommend appropriate resources for obtaining affordable medications

The Development Of A Cancer-Targeting Peptide-Drug Conjugate For The Treatment Of Melanoma, Cassandra Dill

Pharmaceutical Sciences (MS) Theses

Cancer is an ongoing global pandemic which has caused a dramatic shift in research priorities. One of the most aggressive and difficult to treat has invariably remained metastatic melanoma. Although encompassing only 4% of overall skin cancer diagnoses, chances for recovery were slim until recent revolutionary development of immunotherapy adding to its regimen spectrum. This is due to its resistance to many standard-of-care treatment methods, along with its relatively high-metastatic potential. Within the past decade, eight new targeted and immune checkpoint inhibitors have gained FDA approval. The median life survival has increased significantly from 9 months to over 2 years …

Amphiphilic Cell-Penetrating Peptides Containing Natural And Unnatural Amino Acids As Drug Delivery Tools And Antimicrobial Agents, David Salehi

Pharmaceutical Sciences (MS) Theses

Cell-penetrating peptides containing arginine as positively charged residues and tryptophan or diphenylalanine as hydrophobic residues were synthesized. The synthesis was accomplished through the Fmoc solid-phase peptide synthesis in the presence of HBTU and DIPEA. The side-chain protected linear peptides were cleaved from the resin and cyclized in the presence of DIC and HOAt in the solution phase overnight. MALDI-TOF mass spectrometry was used to characterize the peptides.

The cytotoxicity of the synthesized peptides was determined in CCRF-CEM (human, lymphoblast peripheral blood), and HEK-293 (human, embryonic epithelial kidney healthy) cells using the MTS assay. A concentration of 10 µM was found …

Viral Factors Influencing Early Infection Events During Ex-Vivo Kshv Infection, Ramina Nabiee

Pharmaceutical Sciences (PhD) Dissertations

The enigma of Kaposi Sarcoma Herpes Virus infection, and its persistence despite a quarter century of research on the virus, has given rise to an immediate need for addressing fundamental questions about basic immunology and virology knowledge regarding this virus. Kaposi Sarcoma Herpes Virus (KSHV), also known as Human Herpesvirus 8 (HHV8), is the etiological agent of Kaposi Sarcoma (KS) and other lymphoproliferative cancers, such as Multicentric Castleman’s Disease (MCD), Primary Effusion Lymphoma (PEL), and a newly discovered rare disease called KSHV Inflammatory Cytokines Syndrome (KICS). Epidemic KS, also known as AIDS-KS, is the most common cancer in untreated HIV …

Digging Deeper: Improving Health Communication With Patients, Jennifer Ko, Miranda Steinkopf, Abby A. Kahaleh, Sharon Connor

Pharmacy Faculty Books and Book Chapters

At the end of this activity, students will be able to:

• Identify five theories and models that can be used to facilitate the patient-provider health communication process
• Describe opportunities to optimize communication with patients in healthcare settings
• Apply health communication theories within patient care, providing specific approaches and language to utilize

Actividades Profesionales Reservadas En Argentina: Orígenes Y Actualidad / Reserved Professional Activities In Argentina: Origins And Current Situation, Cintia E. Citterio, Héctor Targovnik

Pharmacy Faculty Articles and Research

En Argentina, la Ley de Educación Superior (LES; Ley 24.521, 1995) establece que hay profesiones cuyo ejercicio puede comprometer el interés público poniendo en riesgo de modo directo la salud, la seguridad, los derechos, los bienes o la formación de los habitantes, y las mismas están contempladas en el artículo 43 de la LES. Sólo aquellas actividades que realicen estos profesionales y que implican un riesgo rigurosamente directo, se denominan actividades profesionales reservadas. Pero… ¿Cuál es la diferencia entre actividades profesionales reservadas y alcances de los títulos? ¿Y cómo se establecen? El objetivo de este trabajo es analizar el significado …

Structural Characterization And In Vitro Lipid Binding Studies Of Non-Specific Lipid Transfer Protein 1 (Nsltp1) From Fennel (Foeniculum Vulgare) Seeds, Mekdes Megeressa, Bushra Siraj, Shamshad Zarina, Aftab Ahmed

Pharmacy Faculty Articles and Research

Non-specific lipid transfer proteins (nsLTPs) are cationic proteins involved in intracellular lipid shuttling in growth and reproduction, as well as in defense against pathogenic microbes. Even though the primary and spatial structures of some nsLTPs from different plants indicate their similar features, they exhibit distinct lipid-binding specificities signifying their various biological roles that dictate further structural study. The present study determined the complete amino acid sequence, in silico 3D structure modeling, and the antiproliferative activity of nsLTP1 from fennel (Foeniculum vulgare) seeds. Fennel is a member of the family Umbelliferae (Apiaceae) native to southern Europe and the Mediterranean …

Molecular Virology Of Kshv In The Lymphocyte Compartment—Insights From Patient Samples And De Novo Infection Models, Farizeh Aalam, Jennifer Totonchy

Pharmacy Faculty Articles and Research

The incidence of Kaposi’s sarcoma-associated herpesvirus (KSHV)-associated Kaposi Sarcoma has declined precipitously in the present era of effective HIV treatment. However, KSHV-associated lymphoproliferative disorders although rare, have not seen a similar decline. Lymphoma is now a leading cause of death in people living with HIV (PLWH), indicating that the immune reconstitution provided by antiretroviral therapy is not sufficient to fully correct the lymphomagenic immune dysregulation perpetrated by HIV infection. As such, novel insights into the mechanisms of KSHV-mediated pathogenesis in the immune compartment are urgently needed in order to develop novel therapeutics aimed at prevention and treatment of KSHV-associated lymphoproliferations. …

An Update Of The Virion Proteome Of Kaposi Sarcoma-Associated Herpesvirus, Ramina Nabiee, Basir Syed, Jesus Ramirez Castano, Rukhsana Lalani, Jennifer Totonchy

Pharmacy Faculty Articles and Research

The virion proteins of Kaposi sarcoma-associated herpesvirus (KSHV) were initially characterized in 2005 in two separate studies that combined the detection of 24 viral proteins and a few cellular components via LC-MS/MS or MALDI-TOF. Despite considerable advances in the sensitivity and specificity of mass spectrometry instrumentation in recent years, leading to significantly higher yields in detections, the KSHV virion proteome has not been revisited. In this study, we have re-examined the protein composition of purified KSHV virions via ultra-high resolution Qq time-of-flight mass spectrometry (UHR-QqTOF). Our results confirm the detection of all previously reported virion proteins, in addition to 17 …

Regiospecific Synthesis Of Calcium‐Independent Daptomycin Antibiotics Using A Chemoenzymatic Method, Nagaraju Mupparapu, Yu-Hsin Cindy Lin, Tae Ho Kim, Sherif I. Elshahawi

Pharmacy Faculty Articles and Research

Daptomycin (DAP) is a calcium (Ca2+)‐dependent FDA‐approved antibiotic drug for the treatment of Gram‐positive infections. It possesses a complex pharmacophore hampering derivatization and/or synthesis of analogs. In order to mimic the Ca2+‐binding effect we uses a chemoenzymatic approach to modify the tryptophan (Trp) residue of DAP and synthesize kinetically characterized and structurally elucidated regiospecific Trp‐modified DAP analogs. We demonstrated that the modified DAPs are several‐folds active than the parent molecule against antibiotic‐susceptible and antibiotic‐resistant Gram‐positive bacteria. Strikingly and in contrast to the parent molecule, the DAP derivatives do not rely on calcium or any additional elements for activity.

Seroprevalence Of Novel Coronavirus Sars-Cov-2 At A Community Hospital Emergency Department And Outpatient Laboratory In Northern Orange County, California, Jason Yamaki, Harry Peled, Sajen Mathews, David Park, Mina Firoozi, Kim Smith, Lee Nguyen

Pharmacy Faculty Articles and Research

Introduction

The severe acute respiratory syndrome related coronavirus 2 (SARS-CoV-2) has infected more than 20 million people worldwide, and the spread is most prevalent in the USA, where California had accounted over 240,000 cases in the initial 5 months of the pandemic. To estimate the number of infected persons in our community, we conducted a cross-sectional study to estimate seroprevalence of SARS-CoV-2 infection.

Methods

This cross-sectional study evaluated the presence of immunoglobulin G, antibody for SARS-CoV-2 during the time period of July 15, 2020, to July 27, 2020. Testing was done on serum samples from patients who had visited affiliated …

The Inclusion Of Health Data Standards In The Implementation Of Pharmacogenomics Systems: A Scoping Review, Don Roosan, Angela Hwang, Anandi V. Law, Jay Chok, Moom Roosan

Pharmacy Faculty Articles and Research

Background: Despite potential benefits, the practice of incorporating pharmacogenomics (PGx) results in clinical decisions has yet to diffusewidely. In this study,we conducted a review of recent discussions on data standards and interoperability with a focus on sharing PGx test results among health systems. Materials & methods:We conducted a literature search for PGx clinical decision support systems between 1 January 2012 and 31 January 2020. Thirty-two out of 727 articles were included for the final review. Results: Nine of the 32 articles mentioned data standards and only four of the 32 articles provided solutions for the lack of …

Analysis Of Kshv B Lymphocyte Lineage Tropism In Human Tonsil Reveals Efficient Infection Of Cd138+ Plasma Cells, Farizeh Aalam, Ramina Nabiee, Jesus Ramirez Castano, Jennifer Totonchy

Pharmacy Faculty Articles and Research

Despite 25 years of research, the basic virology of Kaposi Sarcoma Herpesviruses (KSHV) in B lymphocytes remains poorly understood. This study seeks to fill critical gaps in our understanding by characterizing the B lymphocyte lineage-specific tropism of KSHV. Here, we use lymphocytes derived from 40 human tonsil specimens to determine the B lymphocyte lineages targeted by KSHV early during de novo infection in our ex vivo model system. We characterize the immunological diversity of our tonsil specimens and determine that overall susceptibility of tonsil lymphocytes to KSHV infection varies substantially between donors. We demonstrate that a variety of B lymphocyte …

What’S The Big Deal About Statins?, Albert Bach, Jelena Lewis, Susie Yoo

Pharmacy Faculty Articles and Research

"Statins are a group of cholesterol-lowering medications that have been shown evidence to be beneficial for tens of millions of Americans. Some examples of statin medications you may have heard of include: atorvastatin (Lipitor), rosuvastatin (Crestor), simvastatin (Zocor), pravastatin (Pravachol) and lovastatin (Mevacor). Statins are one of the most commonly prescribed medications in the United States. One in four adults over the age of 45 years old are currently taking a statin for its many benefits. See below for more information about its use."

Lc–Ms/Ms-Based In Vitro And In Vivo Investigation Of Blood–Brain Barrier Integrity By Simultaneous Quantitation Of Mannitol And Sucrose, Behnam Noorani, Ekram Ahmed Chowdhury, Faleh Alqahtani, Yeseul Ahn, Dhavalkumar Patel, Abraham Al-Ahmad, Reza Mehvar, Ulrich Bickel

Pharmacy Faculty Articles and Research

Background

Understanding the pathophysiology of the blood brain–barrier (BBB) plays a critical role in diagnosis and treatment of disease conditions. Applying a sensitive and specific LC–MS/MS technique for the measurement of BBB integrity with high precision, we have recently introduced non-radioactive [¹³C₁₂]sucrose as a superior marker substance. Comparison of permeability markers with different molecular weight, but otherwise similar physicochemical properties, can provide insights into the uptake mechanism at the BBB. Mannitol is a small hydrophilic, uncharged molecule that is half the size of sucrose. Previously only radioactive [³H]mannitol or [¹⁴C]mannitol has been …

Overcoming Barriers For Sirna Therapeutics: From Bench To Bedside, Muhammad Imran Sajid, Muhammad Moazzam, Shun Kato, Kayley Yeseom Cho, Rakesh Kumar Tiwari

Pharmacy Faculty Articles and Research

The RNA interference (RNAi) pathway possesses immense potential in silencing any gene in human cells. Small interfering RNA (siRNA) can efficiently trigger RNAi silencing of specific genes. FDA Approval of siRNA therapeutics in recent years garnered a new hope in siRNA therapeutics. However, their therapeutic use is limited by several challenges. siRNAs, being negatively charged, are membrane-impermeable and highly unstable in the systemic circulation. In this review, we have comprehensively discussed the extracellular barriers, including enzymatic degradation of siRNAs by serum endonucleases and RNAases, rapid renal clearance, membrane impermeability, and activation of the immune system. Besides, we have thoroughly described …

Effects Of Germline And Somatic Events In Candidate Brca-Like Genes On Breast-Tumor Signatures, Weston R. Bodily, Brian H. Shirts, Tom Walsh, Suleyman Gulsuner, Mary-Claire King, Alyssa Parker, Moom Roosan, Stephen R. Piccolo

Pharmacy Faculty Articles and Research

Mutations in BRCA1 and BRCA2 cause deficiencies in homologous recombination repair (HR), resulting in repair of DNA double-strand breaks by the alternative non-homologous end-joining pathway, which is more error prone. HR deficiency of breast tumors is important because it is associated with better responses to platinum salt therapies and PARP inhibitors. Among other consequences of HR deficiency are characteristic somatic-mutation signatures and gene-expression patterns. The term “BRCA-like” (or “BRCAness”) describes tumors that harbor an HR defect but have no detectable germline mutation in BRCA1 or BRCA2. A better understanding of the genes and molecular events associated with tumors being …

Cytokine-Targeted Therapeutics For Kshv-Associated Disease, Nedaa Alomari, Jennifer Totonchy

Pharmacy Faculty Articles and Research

Kaposi’s sarcoma-associated herpesvirus (KSHV) also known as human herpesvirus 8 (HHV-8), is linked to several human malignancies including Kaposi sarcoma (KS), primary effusion lymphoma (PEL), multicentric Castleman’s disease (MCD) and recently KSHV inflammatory cytokine syndrome (KICS). As with other diseases that have a significant inflammatory component, current therapy for KSHV-associated disease is associated with significant off-target effects. However, recent advances in our understanding of the pathogenesis of KSHV have produced new insight into the use of cytokines as potential therapeutic targets. Better understanding of the role of cytokines during KSHV infection and tumorigenesis may lead to new preventive or therapeutic …

Parent Responses To Pediatric Pain: The Differential Effects Of Ethnicity On Opioid Consumption, Candice D. Donaldson, Brooke N. Jenkins, Michelle A. Fortier, Michael T. Phan, Daniel M. Tomaszewski, Sun Yang, Zeev N. Kain

Psychology Faculty Articles and Research

Objective

Within the context of the United States opioid epidemic, some parents often fear the use of opioids to help manage their children's postoperative pain. As a possible consequence, parents often do not dispense optimal analgesic medications to their children after surgery, putting their children at risk of suffering from postsurgical pain. The objective of this research was to assess ethnicity as a predictor of both pain and opioid consumption, and to examine how Hispanic/Latinx and Non-Hispanic White parents alter their child's opioid consumption in response to significant postsurgical pain.

Methods

Participants were 254 children undergoing outpatient tonsillectomy and/or adenoidectomy …

Artificial Intelligence–Powered Smartphone App To Facilitate Medication Adherence: Protocol For A Human Factors Design Study, Don Roosan, Jay Chok, Mazharul Karim, Anandi V. Law, Andrius Baskys, Angela Hwang, Moom Roosan

Pharmacy Faculty Articles and Research

Background: Medication Guides consisting of crucial interactions and side effects are extensive and complex. Due to the exhaustive information, patients do not retain the necessary medication information, which can result in hospitalizations and medication nonadherence. A gap exists in understanding patients’ cognition of managing complex medication information. However, advancements in technology and artificial intelligence (AI) allow us to understand patient cognitive processes to design an app to better provide important medication information to patients.

Objective: Our objective is to improve the design of an innovative AI- and human factor–based interface that supports patients’ medication information comprehension that could potentially …

Acute And Chronic Dosing Of A High-Affinity Rat/Mouse Chimeric Transferrin Receptor Antibody In Mice, Demi M. Castellanos, Jiahong Sun, Joshua Yang, Weijun Ou, Alexander C. Zambon, William M. Pardridge, Rachita K. Sumbria

Pharmacy Faculty Articles and Research

Non-invasive brain delivery of neurotherapeutics is challenging due to the blood-brain barrier. The revived interest in transferrin receptor antibodies (TfRMAbs) as brain drug-delivery vectors has revealed the effect of dosing regimen, valency, and affinity on brain uptake, TfR expression, and Fc-effector function side effects. These studies have primarily used monovalent TfRMAbs with a human constant region following acute intravenous dosing in mice. The effects of a high-affinity bivalent TfRMAb with a murine constant region, without a fusion partner, following extravascular dosing in mice are, however, not well characterized. Here we elucidate the plasma pharmacokinetics and safety of a high-affinity bivalent …

Click-Free Synthesis Of A Multivalent Tricyclic Peptide As A Molecular Transporter, Sumit Kumar, Dindyal Mandal, Shaima Ahmed El-Mowafi, Saghar Mozaffari, Rakesh Kumar Tiwari, Keykavous Parang

Pharmacy Faculty Articles and Research

The cellular delivery of cell-impermeable and water-insoluble molecules remains an ongoing challenge to overcome. Previously, we reported amphipathic cyclic peptides c[WR]₄ and c[WR]₅ consisting of alternate arginine and tryptophan residues as nuclear-targeting molecular transporters. These peptides contain an optimal balance of positive charge and hydrophobicity, which is required for interactions with the phospholipid bilayer to facilitate their application as a drug delivery system. To further optimize them, we synthesized and evaluated a multivalent tricyclic peptide as an efficient molecular transporter. The monomeric cyclic peptide building blocks were synthesized using Fmoc/tBu solid-phase chemistry and cyclization in the …

Effect Of High Glucose On Ocular Surface Epithelial Cell Barrier And Tight Junction Proteins, Saleh M. Alfuraih, Ashley Barbarino, Christopher Ross, Kiumars Shamloo, Vishal Jhanji, Miao Zhang, Ajay Sharma

Pharmacy Faculty Articles and Research

PURPOSE. Patients with diabetes mellitus are reported to have ocular surface defects, impaired ocular surface barrier function, and a higher incidence of corneal and conjunctival infections. Tight junctions are critical for ocular surface barrier function. The present study was designed to investigate the effect of high glucose exposure on human corneal and conjunctival epithelial cell barrier function and tight junction proteins.

METHODS. Human corneal and conjunctival epithelial cells were exposed to 15 mM and 30 mM glucose for 24 and 72 hours. The barrier function was measured using transepithelial electrical resistance (TEER). The cell migration was quantified using scratch assay. …

Hydrophobic Interactions Between The Ha Helix And S4‐S5 Linker Modulate Apparent Ca2+ Sensitivity Of Sk2 Channels, Young-Woo Nam, Meng Cui, Razan Orfali, Adam Viegas, Misa Nguyen, Eman H. M. Mohammed, Khalid Zoghebi, Simin Rahighi, Keykavous Parang, Miao Zhang

Pharmacy Faculty Articles and Research

Aim

Small‐conductance Ca²⁺‐activated potassium (SK) channels are activated exclusively by increases in intracellular Ca²⁺, that binds to calmodulin constitutively associated with the channel. Wild‐type SK2 channels are activated by Ca²⁺ with an EC50 value of ~0.3 μM. Here, we investigate hydrophobic interactions between the HA helix and the S4‐S5 linker as a major determinant of channel apparent Ca²⁺ sensitivity.

Methods

site‐directed mutagenesis, electrophysiological recordings and molecular dynamic (MD) simulations were utilized.

Results

Mutations that decrease hydrophobicity at the HA‐S4‐S5 interface lead to Ca²⁺ hyposensitivity of SK2 channels. Mutations that increase hydrophobicity result in …