The LRRC family of BK channel regulatory subunits: potential roles in health and disease

2022 ◽  
Author(s):  
Vivian Gonzalez‐Perez ◽  
Yu Zhou ◽  
Matthew A. Ciorba ◽  
Christopher J. Lingle
Keyword(s):  
Bk Channel ◽  
Regulatory Subunits ◽  
Health And Disease

scholarly journals Regulatory γ1 subunits defy symmetry in functional modulation of BK channels

2018 ◽  
Vol 115 (40) ◽  
pp. 9923-9928 ◽  
Author(s):  
Vivian Gonzalez-Perez ◽  
Manu Ben Johny ◽  
Xiao-Ming Xia ◽  
Christopher J. Lingle
Keyword(s):  
Single Channel ◽  
Regulatory Protein ◽  
Resonance Energy Transfer ◽  
Resonance Energy ◽  
Bk Channels ◽  
Bk Channel ◽  
Single Type ◽  
Regulatory Subunits ◽  
And Function

Structural symmetry is a hallmark of homomeric ion channels. Nonobligatory regulatory proteins can also critically define the precise functional role of such channels. For instance, the pore-forming subunit of the large conductance voltage and calcium-activated potassium (BK, Slo1, or KCa1.1) channels encoded by a single KCa1.1 gene assembles in a fourfold symmetric fashion. Functional diversity arises from two families of regulatory subunits, β and γ, which help define the range of voltages over which BK channels in a given cell are activated, thereby defining physiological roles. A BK channel can contain zero to four β subunits per channel, with each β subunit incrementally influencing channel gating behavior, consistent with symmetry expectations. In contrast, a γ1 subunit (or single type of γ1 subunit complex) produces a functionally all-or-none effect, but the underlying stoichiometry of γ1 assembly and function remains unknown. Here we utilize two distinct and independent methods, a Forster resonance energy transfer-based optical approach and a functional reporter in single-channel recordings, to reveal that a BK channel can contain up to four γ1 subunits, but a single γ1 subunit suffices to induce the full gating shift. This requires that the asymmetric association of a single regulatory protein can act in a highly concerted fashion to allosterically influence conformational equilibria in an otherwise symmetric K+channel.

scholarly journals Regulation of large conductance calcium- and voltage-activated potassium (BK) channels by S-palmitoylation

2013 ◽  
Vol 41 (1) ◽  
pp. 67-71 ◽  
Author(s):  
Michael J. Shipston
Keyword(s):  
Surface Expression ◽  
Bk Channels ◽  
Bk Channel ◽  
Post Translational Modification ◽  
Physiological Control ◽  
Α Subunit ◽  
Channel Trafficking ◽  
C Terminus ◽  
Family Protein ◽  
Health And Disease

BK (large conductance calcium- and voltage-activated potassium) channels are important determinants of physiological control in the nervous, endocrine and vascular systems with channel dysfunction associated with major disorders ranging from epilepsy to hypertension and obesity. Thus the mechanisms that control channel surface expression and/or activity are important determinants of their (patho)physiological function. BK channels are S-acylated (palmitoylated) at two distinct sites within the N- and C-terminus of the pore-forming α-subunit. Palmitoylation of the N-terminus controls channel trafficking and surface expression whereas palmitoylation of the C-terminal domain determines regulation of channel activity by AGC-family protein kinases. Recent studies are beginning to reveal mechanistic insights into how palmitoylation controls channel trafficking and cross-talk with phosphorylation-dependent signalling pathways. Intriguingly, each site of palmitoylation is regulated by distinct zDHHCs (palmitoyl acyltransferases) and APTs (acyl thioesterases). This supports that different mechanisms may control substrate specificity by zDHHCs and APTs even within the same target protein. As palmitoylation is dynamically regulated, this fundamental post-translational modification represents an important determinant of BK channel physiology in health and disease.

scholarly journals Regulation of BK Channels by Beta and Gamma Subunits

2019 ◽  
Vol 81 (1) ◽  
pp. 113-137 ◽  
Author(s):  
Vivian Gonzalez-Perez ◽  
Christopher J. Lingle
Keyword(s):  
Functional Properties ◽  
Splice Variants ◽  
Bk Channels ◽  
Bk Channel ◽  
Diverse Range ◽  
Α Subunit ◽  
Regulatory Subunits ◽  
Gamma Subunits ◽  
Specific Alternative ◽  
Alternative Splice Variants

Ca2+- and voltage-gated K+ channels of large conductance (BK channels) are expressed in a diverse variety of both excitable and inexcitable cells, with functional properties presumably uniquely calibrated for the cells in which they are found. Although some diversity in BK channel function, localization, and regulation apparently arises from cell-specific alternative splice variants of the single pore–forming α subunit ( KCa1.1, Kcnma1, Slo1) gene, two families of regulatory subunits, β and γ, define BK channels that span a diverse range of functional properties. We are just beginning to unravel the cell-specific, physiological roles served by BK channels of different subunit composition.

scholarly journals Two classes of regulatory subunits coassemble in the same BK channel and independently regulate gating

2015 ◽  
Vol 6 (1) ◽  
Author(s):  
Vivian Gonzalez-Perez ◽  
Xiao-Ming Xia ◽  
Christopher J. Lingle
Keyword(s):  
Bk Channel ◽  
Regulatory Subunits

scholarly journals Variants of the KCNMB3 regulatory subunit of maxi BK channels affect channel inactivation

2003 ◽  
Vol 15 (3) ◽  
pp. 191-198 ◽  
Author(s):  
Song Hu ◽  
Malgorzata Z. Labuda ◽  
Massimo Pandolfo ◽  
Greg G. Goss ◽  
Heather E. McDermid ◽  
...  
Keyword(s):  
Time Course ◽  
Bk Channels ◽  
Bk Channel ◽  
Idiopathic Epilepsy ◽  
Regulatory Subunit ◽  
Kinetic Properties ◽  
Regulatory Subunits ◽  
Channel Inactivation ◽  
Current Voltage ◽  
Calcium Activated Potassium Channels

The steady-state and kinetic properties of the KCNMB3 regulatory subunits associated with calcium-activated potassium channels (BK channels) are presented. BK channels containing four sequence variants (V1–V4) in the four different isoforms of the β-subunit (β3a, β3b, β3c, and β3d) were expressed in Xenopus oocytes. Reconstituted BK channel inactivation ranged from none to around 90% inactivation. In particular, channels expressing the β3b-V4 variant displayed a right shift in the potassium current voltage-dependence of activation and inactivated to about 30% of the maximum conductance, compared with wild-type β3b channels that showed no inactivation. When the membrane potential was depolarized, BK channels inactivated with a very rapid time course (∼2–6 ms). This same variant was previously demonstrated to show subtly higher incidence in patients with idiopathic epilepsy (IE) compared with controls, especially when combined with variant V2 (combined heterozygotes). Furthermore, the gene maps to a region containing a susceptibility factor for this disorder. Taken together, these data suggest that neurons expressing BK channels composed of the β3b-V4 variant subunit may experience reduced levels of inhibition and may therefore play permissive roles in high levels of neuronal activity that is characteristic of epilepsy.

scholarly journals Structure of eukaryotic DNA polymerase δ bound to the PCNA clamp while encircling DNA

2020 ◽  
Vol 117 (48) ◽  
pp. 30344-30353
Author(s):  
Fengwei Zheng ◽  
Roxana E. Georgescu ◽  
Huilin Li ◽  
Michael E. O’Donnell
Keyword(s):  
Dna Polymerase ◽  
Human Cancer ◽  
Catalytic Subunit ◽  
Nuclear Antigen ◽  
Genome Replication ◽  
Regulatory Subunits ◽  
Minimum Drag ◽  
Disease Mutations ◽  
Eukaryotic Dna ◽  
Health And Disease

The DNA polymerase (Pol) δ ofSaccharomyces cerevisiae(S.c.) is composed of the catalytic subunit Pol3 along with two regulatory subunits, Pol31 and Pol32. Pol δ binds to proliferating cell nuclear antigen (PCNA) and functions in genome replication, repair, and recombination. Unique among DNA polymerases, the Pol3 catalytic subunit contains a 4Fe-4S cluster that may sense the cellular redox state. Here we report the 3.2-Å cryo-EM structure of S.c. Pol δ in complex with primed DNA, an incoming ddTTP, and the PCNA clamp. Unexpectedly, Pol δ binds only one subunit of the PCNA trimer. This singular yet extensive interaction holds DNA such that the 2-nm-wide DNA threads through the center of the 3-nm interior channel of the clamp without directly contacting the protein. Thus, a water-mediated clamp and DNA interface enables the PCNA clamp to “waterskate” along the duplex with minimum drag. Pol31 and Pol32 are positioned off to the side of the catalytic Pol3-PCNA-DNA axis. We show here that Pol31-Pol32 binds single-stranded DNA that we propose underlies polymerase recycling during lagging strand synthesis, in analogy toEscherichia colireplicase. Interestingly, the 4Fe-4S cluster in the C-terminal CysB domain of Pol3 forms the central interface to Pol31-Pol32, and this strategic location may explain the regulation of the oxidation state on Pol δ activity, possibly useful during cellular oxidative stress. Importantly, human cancer and other disease mutations map to nearly every domain of Pol3, suggesting that all aspects of Pol δ replication are important to human health and disease.

scholarly journals Mitochondrial Calcium Uniporter Structure and Function in Different Types of Muscle Tissues in Health and Disease

2019 ◽  
Vol 20 (19) ◽  
pp. 4823 ◽  
Author(s):  
Nadezhda Tarasova ◽  
Polina Vishnyakova ◽  
Yulia Logashina ◽  
Andrey Elchaninov
Keyword(s):  
Mitochondrial Calcium ◽  
Inner Mitochondrial Membrane ◽  
Regulatory Subunits ◽  
Mitochondrial Calcium Uniporter ◽  
Calcium Uniporter ◽  
Muscle Tissues ◽  
Different Types ◽  
Health And Disease ◽  
The Moment ◽  
And Function

Calcium ions (Ca2+) influx to mitochondrial matrix is crucial for the life of a cell. Mitochondrial calcium uniporter (mtCU) is a protein complex which consists of the pore-forming subunit (MCU) and several regulatory subunits. MtCU is the main contributor to inward Ca2+ currents through the inner mitochondrial membrane. Extensive investigations of mtCU involvement into normal and pathological molecular pathways started from the moment of discovery of its molecular components. A crucial role of mtCU in the control of these pathways is now recognized in both health and disease. In particular, impairments of mtCU function have been demonstrated for cardiovascular and skeletal muscle-associated pathologies. This review summarizes the current state of knowledge on mtCU structure, regulation, and function in different types of muscle tissues in health and disease.

Drug Induced Changes in Cell Organelles

1968 ◽  
Vol 26 ◽  
pp. 110-111
Author(s):  
Sarah A. Luse
Keyword(s):  
Clinical Medicine ◽  
Cell Organelles ◽  
Riboflavin Deficiency ◽  
Drug Induced ◽  
New Era ◽  
Health And Disease ◽  
In The Beginning ◽  
Cellular Pathology ◽  
Induced Changes ◽  
The Impact

In the mid-nineteenth century Virchow revolutionized pathology by introduction of the concept of “cellular pathology”. Today, a century later, this term has increasing significance in health and disease. We now are in the beginning of a new era in pathology, one which might well be termed “organelle pathology” or “subcellular pathology”. The impact of lysosomal diseases on clinical medicine exemplifies this role of pathology of organelles in elucidation of disease today.Another aspect of cell organelles of prime importance is their pathologic alteration by drugs, toxins, hormones and malnutrition. The sensitivity of cell organelles to minute alterations in their environment offers an accurate evaluation of the site of action of drugs in the study of both function and toxicity. Examples of mitochondrial lesions include the effect of DDD on the adrenal cortex, riboflavin deficiency on liver cells, elevated blood ammonia on the neuron and some 8-aminoquinolines on myocardium.

The Laryngeal Epithelium in Reflux

2011 ◽  
Vol 21 (3) ◽  
pp. 112-117 ◽  
Author(s):  
Elizabeth Erickson-Levendoski ◽  
Mahalakshmi Sivasankar
Keyword(s):  
Laryngopharyngeal Reflux ◽  
Critical Role ◽  
Structure And Function ◽  
Laryngeal Disease ◽  
Health And Disease ◽  
And Function ◽  
The Impact

The epithelium plays a critical role in the maintenance of laryngeal health. This is evident in that laryngeal disease may result when the integrity of the epithelium is compromised by insults such as laryngopharyngeal reflux. In this article, we will review the structure and function of the laryngeal epithelium and summarize the impact of laryngopharyngeal reflux on the epithelium. Research investigating the ramifications of reflux on the epithelium has improved our understanding of laryngeal disease associated with laryngopharyngeal reflux. It further highlights the need for continued research on the laryngeal epithelium in health and disease.

Studies on Gastric Mucus in Health and Disease

1965 ◽  
Vol 48 (6) ◽  
pp. 758-767 ◽  
Author(s):  
Lansing C. Hoskins ◽  
Norman Zamcheck
Keyword(s):  
Gastric Mucus ◽  
Health And Disease
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