f/HCN channels: from a tiny current controlling cardiac pacemaking to a pleiotropic current all over the body.

2021 ◽  
Author(s):  
Annalisa Bucchia ◽  
Mirko Baruscottia ◽  
Andrea Barbutia
Keyword(s):  
The Body ◽  
Hcn Channels ◽  
Cardiac Pacemaking

scholarly journals The HCN Channel Voltage Sensor Undergoes A Large Downward Motion During Hyperpolarization

2019 ◽  
Author(s):  
Gucan Dai ◽  
Teresa K. Aman ◽  
Frank DiMaio ◽  
William N. Zagotta
Keyword(s):  
Ion Channels ◽  
Metal Ion ◽  
Voltage Sensor ◽  
The Body ◽  
Resting Membrane Potential ◽  
Hcn Channels ◽  
Hcn Channel ◽  
Open Probability ◽  
Membrane Hyperpolarization ◽  
Transmembrane Voltage

Voltage-gated ion channels (VGICs) underlie almost all electrical signaling in the body1. They change their open probability in response to changes in transmembrane voltage, allowing permeant ions to flow across the cell membrane. Ion flow through VGICs underlies numerous physiological processes in excitable cells1. In particular, hyperpolarization-activated cyclic nucleotide-gated (HCN) channels, which operate at the threshold of excitability, are essential for pacemaking activity, resting membrane potential, and synaptic integration2. VGICs contain a series of positively-charged residues that are displaced in response to changes in transmembrane voltage, resulting in a conformational change that opens the pore3–6. These voltage-sensing charges, which reside in the S4 transmembrane helix of the voltage-sensor domain (VSD)3 and within the membrane’s electric field, are thought to move towards the inside of the cell (downwards) during membrane hyperpolarization7. HCN channels are unique among VGICs because their open probability is increased by membrane hyperpolarization rather than depolarization8–10. The mechanism underlying this “reverse gating” is still unclear. Moreover, although many X-ray crystal and cryo-EM structures have been solved for the depolarized state of the VSD, including that of HCN channels11, no structures have been solved at hyperpolarized voltages. Here we measure the precise movement of the charged S4 helix of an HCN channel using transition metal ion fluorescence resonance energy transfer (tmFRET). We show that the S4 undergoes a significant (~10 Å) downward movement in response to membrane hyperpolarization. Furthermore, by applying constraints determined from tmFRET experiments to Rosetta modeling, we reveal that the carboxyl-terminal part of the S4 helix exhibits an unexpected tilting motion during hyperpolarization activation. These data provide a long-sought glimpse of the hyperpolarized state of a functioning VSD and also a framework for understanding the dynamics of reverse gating in HCN channels. Our methods can be broadly applied to probe short-distance rearrangements in other ion channels and membrane proteins.

scholarly journals State-dependent and site-directed photodynamic transformation of HCN2 channel by singlet oxygen

2014 ◽  
Vol 143 (5) ◽  
pp. 633-644 ◽  
Author(s):  
Weihua Gao ◽  
Zhuocheng Su ◽  
Qinglian Liu ◽  
Lei Zhou
Keyword(s):  
Singlet Oxygen ◽  
Basic Research ◽  
Laser Pulses ◽  
Inhibitory Effect ◽  
Biological Molecules ◽  
Hcn Channels ◽  
State Dependent ◽  
C Terminus ◽  
Instantaneous Current ◽  
Cardiac Pacemaking

Singlet oxygen (1O2), which is generated through metabolic reactions and oxidizes numerous biological molecules, has been a useful tool in basic research and clinical practice. However, its role as a signaling factor, as well as a mechanistic understanding of the oxidation process, remains poorly understood. Here, we show that hyperpolarization-activated, cAMP-gated (HCN) channels–which conduct the hyperpolarization-activated current (Ih) and the voltage-insensitive instantaneous current (Iinst), and contribute to diverse physiological functions including learning and memory, cardiac pacemaking, and the sensation of pain–are subject to modification by 1O2. To increase the site specificity of 1O2 generation, we used fluorescein-conjugated cAMP, which specifically binds to HCN channels, or a chimeric channel in which an in-frame 1O2 generator (SOG) protein was fused to the HCN C terminus. Millisecond laser pulses reduced Ih current amplitude, slowed channel deactivation, and enhanced Iinst current. The modification of HCN channel function is a photodynamic process that involves 1O2, as supported by the dependence on dissolved oxygen in solutions, the inhibitory effect by a 1O2 scavenger, and the results with the HCN2-SOG fusion protein. Intriguingly, 1O2 modification of the HCN2 channel is state dependent: laser pulses applied to open channels mainly slow down deactivation and increase Iinst, whereas for the closed channels, 1O2 modification mainly reduced Ih amplitude. We identified a histidine residue (H434 in S6) near the activation gate in the pore critical for 1O2 modulation of HCN function. Alanine replacement of H434 abolished the delay in channel deactivation and the generation of Iinst induced by photodynamic modification. Our study provides new insights into the instantaneous current conducted by HCN channels, showing that modifications to the region close to the intracellular gate underlie the expression of Iinst, and establishes a well-defined model for studying 1O2 modifications at the molecular level.

HCN Channels and Cardiac Pacemaking

2018 ◽  
pp. 97-126
Author(s):  
Annalisa Bucchi ◽  
Chiara Piantoni ◽  
Andrea Barbuti ◽  
Dario DiFrancesco ◽  
Mirko Baruscotti
Keyword(s):  
Hcn Channels ◽  
Cardiac Pacemaking

Representing utility and deploying the body

2020 ◽  
Vol 43 ◽  
Author(s):  
David Spurrett
Keyword(s):  
Functional Activity ◽  
Degrees Of Freedom ◽  
The Body ◽  
Target Article ◽  
Processing Demands ◽  
The Many

Abstract Comprehensive accounts of resource-rational attempts to maximise utility shouldn't ignore the demands of constructing utility representations. This can be onerous when, as in humans, there are many rewarding modalities. Another thing best not ignored is the processing demands of making functional activity out of the many degrees of freedom of a body. The target article is almost silent on both.

Neuron-glia relationship during the early postembryonic development of the nervous system in some oligochaetes

1978 ◽  
Vol 36 (2) ◽  
pp. 600-601
Author(s):  
Wiktor Djaczenko ◽  
Carmen Calenda Cimmino
Keyword(s):  
Nervous System ◽  
Glial Cells ◽  
Early Period ◽  
Postembryonic Development ◽  
Ruthenium Red ◽  
The Body ◽  
Tubifex Tubifex ◽  
Growth Stages ◽  
Cell Processes ◽  
Cytoplasmic Processes

The simplicity of the developing nervous system of oligochaetes makes of it an excellent model for the study of the relationships between glia and neurons. In the present communication we describe the relationships between glia and neurons in the early periods of post-embryonic development in some species of oligochaetes.Tubifex tubifex (Mull. ) and Octolasium complanatum (Dugès) specimens starting from 0. 3 mm of body length were collected from laboratory cultures divided into three groups each group fixed separately by one of the following methods: (a) 4% glutaraldehyde and 1% acrolein fixation followed by osmium tetroxide, (b) TAPO technique, (c) ruthenium red method.Our observations concern the early period of the postembryonic development of the nervous system in oligochaetes. During this period neurons occupy fixed positions in the body the only observable change being the increase in volume of their perikaryons. Perikaryons of glial cells were located at some distance from neurons. Long cytoplasmic processes of glial cells tended to approach the neurons. The superimposed contours of glial cell processes designed from electron micrographs, taken at the same magnification, typical for five successive growth stages of the nervous system of Octolasium complanatum are shown in Fig. 1. Neuron is designed symbolically to facilitate the understanding of the kinetics of the growth process.

Flagellar Attachment in Selected Trypanosomes

1973 ◽  
Vol 31 ◽  
pp. 496-497
Author(s):  
J. J. Paulin
Keyword(s):  
Cell Membrane ◽  
Lateral Surface ◽  
The Body ◽  
Flagellar Pocket ◽  
Integral Component ◽  
Free Flagellum ◽  
Flagellar Axoneme

Movement in epimastigote and trypomastigote stages of trypanosomes is accomplished by planar sinusoidal beating of the anteriorly directed flagellum and associated undulating membrane. The flagellum emerges from a bottle-shaped depression, the flagellar pocket, opening on the lateral surface of the cell. The limiting cell membrane envelopes not only the body of the trypanosome but is continuous with and insheathes the flagellar axoneme forming the undulating membrane. In some species a paraxial rod parallels the axoneme from its point of emergence at the flagellar pocket and is an integral component of the undulating membrane. A portion of the flagellum may extend beyond the anterior apex of the cell as a free flagellum; the length is variable in different species of trypanosomes.

Otoconia formation in the chick embryo

1983 ◽  
Vol 41 ◽  
pp. 572-573
Author(s):  
C.D. Fermin ◽  
M. Igarashi
Keyword(s):  
Chick Embryo ◽  
Inner Ear ◽  
Gallus Domesticus ◽  
The Body ◽  
Abnormal Behavior ◽  
Intensive Study ◽  
Basic Fuchsin ◽  
Gestational Period ◽  
Sensory Epithelia ◽  
Transmission Electron

Otoconia are microscopic geometric structures that cover the sensory epithelia of the utricle and saccule (gravitational receptors) of mammals, and the lagena macula of birds. The importance of otoconia for maintanance of the body balance is evidenced by the abnormal behavior of species with genetic defects of otolith. Although a few reports have dealt with otoconia formation, some basic questions remain unanswered. The chick embryo is desirable for studying otoconial formation because its inner ear structures are easily accessible, and its gestational period is short (21 days of incubation).The results described here are part of an intensive study intended to examine the morphogenesis of the otoconia in the chick embryo (Gallus- domesticus) inner ear. We used chick embryos from the 4th day of incubation until hatching, and examined the specimens with light (LM) and transmission electron microscopy (TEM). The embryos were decapitated, and fixed by immersion with 3% cold glutaraldehyde. The ears and their parts were dissected out under the microscope; no decalcification was used. For LM, the ears were embedded in JB-4 plastic, cut serially at 5 micra and stained with 0.2% toluidine blue and 0.1% basic fuchsin in 25% alcohol.

Voids in Irradiated Tungsten and Molybdenum

1969 ◽  
Vol 27 ◽  
pp. 190-191
Author(s):  
Robert C. Rau ◽  
Robert L. Ladd
Keyword(s):  
Melting Point ◽  
Fast Neutron ◽  
Neutron Irradiation ◽  
Elevated Temperatures ◽  
Irradiation Temperature ◽  
The Body ◽  
Face Centered Cubic ◽  
Body Centered Cubic ◽  
Cubic Metals ◽  
Face Centered

Recent studies have shown the presence of voids in several face-centered cubic metals after neutron irradiation at elevated temperatures. These voids were found when the irradiation temperature was above 0.3 Tm where Tm is the absolute melting point, and were ascribed to the agglomeration of lattice vacancies resulting from fast neutron generated displacement cascades. The present paper reports the existence of similar voids in the body-centered cubic metals tungsten and molybdenum.

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