Evolution and structural diversification of hyperpolarization-activated cyclic nucleotide-gated channel genes

2007 ◽  
Vol 29 (3) ◽  
pp. 231-245 ◽  
Author(s):  
Heather A. Jackson ◽  
Christian R. Marshall ◽  
Eric A. Accili
Keyword(s):  
Cyclic Nucleotide ◽  
Phylogenetic Analyses ◽  
Critical Role ◽  
Hcn Channels ◽  
Ancestral Gene ◽  
Conserved Sequence ◽  
Gated Channel ◽  
Duplication Events ◽  
The Individual ◽  
And Function

Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels are members of the voltage-gated channel superfamily and play a critical role in cellular pace-making. Overall sequence conservation is high throughout the family, and channel functions are similar but not identical. Phylogenetic analyses are imperative to understand how these genes have evolved and to make informed comparisons of HCN structure and function. These have been previously limited, however, by the small number of available sequences, from a minimal number of species unevenly distributed over evolutionary time. We have now identified and annotated 31 novel genes from invertebrates, urochordates, fish, amphibians, birds, and mammals. With increased sequence numbers and a broader species representation, a more precise sequence comparison was performed and an evolutionary history for these genes was constructed. Our data confirm the existence of at least four vertebrate paralogs and suggest that these arose via three duplication and diversification events from a single ancestral gene. Additional lineage-specific duplications appear to have occurred in urochordate and fish genomes. Based on exon boundary conservation and phylogenetic analyses, we hypothesize that mammalian gene structure was established, and duplication events occurred, after the divergence of urochordates and before the divergence of fish from the tetrapod lineage. In addition, we identified highly conserved sequence regions that are likely important for general HCN functions, as well as regions with differences conserved among each of the individual paralogs. The latter may underlie more subtle isoform-specific properties that are otherwise masked by the high identity among mammalian orthologs and/or inaccurate alignments between paralogs.

Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels as Drug Targets for Neurological Disorders

2020 ◽  
Vol 60 (1) ◽  
pp. 109-131 ◽  
Author(s):  
Bina Santoro ◽  
Mala M. Shah
Keyword(s):  
Neuronal Activity ◽  
Cyclic Nucleotide ◽  
Neurological Disorders ◽  
Drug Targets ◽  
Neuronal Excitability ◽  
Current Knowledge ◽  
Hcn Channels ◽  
Voltage Gated Ion Channels ◽  
The Individual ◽  
And Function

The hyperpolarization-activated cyclic nucleotide-gated (HCN) channels are voltage-gated ion channels that critically modulate neuronal activity. Four HCN subunits ( HCN1–4) have been cloned, each having a unique expression profile and distinctive effects on neuronal excitability within the brain. Consistent with this, the expression and function of these subunits are altered in diverse ways in neurological disorders. Here, we review current knowledge on the structure and distribution of the individual HCN channel isoforms, their effects on neuronal activity under physiological conditions, and how their expression and function are altered in neurological disorders, particularly epilepsy, neuropathic pain, and affective disorders. We discuss the suitability of HCN channels as therapeutic targets and how drugs might be strategically designed to specifically act on particular isoforms. We conclude that medicines that target individual HCN isoforms and/or their auxiliary subunit, TRIP8b, may provide valuable means of treating distinct neurological conditions.

scholarly journals The BAHD Gene Family in Cacao (Theobroma cacao, Malvaceae): Genome-Wide Identification and Expression Analysis

2021 ◽  
Vol 9 ◽  
Author(s):  
Abdullah ◽  
Sahar Faraji ◽  
Parviz Heidari ◽  
Péter Poczai
Keyword(s):  
Gene Family ◽  
Theobroma Cacao ◽  
Critical Role ◽  
Divergence Time ◽  
Purifying Selection ◽  
Plant Metabolites ◽  
Corchorus Capsularis ◽  
Cell Stability ◽  
Duplication Events ◽  
And Function

The benzyl alcohol O-acetyl transferase, anthocyanin O-hydroxycinnamoyl transferase, N-hydroxycinnamoyl anthranilate benzoyl transferase, and deacetylvindoline 4-O-acetyltransferase (BAHD) enzymes play a critical role in regulating plant metabolites and affecting cell stability. In the present study, members of the BAHD gene family were recognized in the genome of Theobroma cacao and characterized using various bioinformatics tools. We found 27 non-redundant putative tcBAHD genes in cacao for the first time. Our findings indicate that tcBAHD genes are diverse based on sequence structure, physiochemical properties, and function. When analyzed with BAHDs of Gossypium raimondii and Corchorus capsularis clustered into four main groups. According to phylogenetic analysis, BAHD genes probably evolved drastically after their divergence. The divergence time of duplication events with purifying selection pressure was predicted to range from 1.82 to 15.50 MYA. Pocket analysis revealed that serine amino acid is more common in the binding site than other residuals, reflecting its key role in regulating the activity of tcBAHDs. Furthermore, cis-acting elements related to the responsiveness of stress and hormone, particularly ABA and MeJA, were frequently observed in the promoter region of tcBAHD genes. RNA-seq analysis further illustrated that tcBAHD13 and tcBAHD26 are involved in response to Phytophthora megakarya fungi. In conclusion, it is likely that evolutionary processes, such as duplication events, have caused high diversity in the structure and function of tcBAHD genes.

scholarly journals N-Cadherin Is Critical for the Survival of Germ Cells, the Formation of Steroidogenic Cells, and the Architecture of Developing Mouse Gonads

Cells ◽  
2019 ◽  
Vol 8 (12) ◽  
pp. 1610 ◽  
Author(s):  
Rafal P. Piprek ◽  
Michal Kolasa ◽  
Dagmara Podkowa ◽  
Malgorzata Kloc ◽  
Jacek Z. Kubiak
Keyword(s):  
Germ Cells ◽  
Hormonal Regulation ◽  
Critical Role ◽  
Somatic Cells ◽  
Gonad Development ◽  
Knock Out ◽  
Gonad Differentiation ◽  
Steroidogenic Cells ◽  
The Individual ◽  
And Function

Normal gonad development assures the fertility of the individual. The properly functioning gonads must contain a sufficient number of the viable germ cells, possess a correct architecture and tissue structure, and assure the proper hormonal regulation. This is achieved by the interplay between the germ cells and different types of somatic cells. N-cadherin coded by the Cdh2 gene plays a critical role in this interplay. To gain an insight into the role of N-cadherin in the development of mouse gonads, we used the Cre-loxP system to knock out N-cadherin separately in two cell lines: the SF1+ somatic cells and the OCT4+ germ cells. We observed that N-cadherin plays a key role in the survival of both female and male germ cells. However, the N-cadherin is not necessary for the differentiation of the Sertoli cells or the initiation of the formation of testis cords or ovigerous cords. In the later stages of gonad development, N-cadherin is important for the maintenance of testis cord structure and is required for the formation of steroidogenic cells. In the ovaries, N-cadherin is necessary for the formation of the ovarian follicles. These results indicate that N-cadherin plays a major role in gonad differentiation, structuralization, and function.

scholarly journals Critical role for hyperpolarization-activated cyclic nucleotide-gated channel 2 in the AIF-mediated apoptosis

2010 ◽  
Vol 29 (22) ◽  
pp. 3869-3878 ◽  
Author(s):  
Erik Norberg ◽  
Marie Karlsson ◽  
Olga Korenovska ◽  
Susanne Szydlowski ◽  
Gilad Silberberg ◽  
...  
Keyword(s):  
Cyclic Nucleotide ◽  
Critical Role ◽  
Gated Channel

Mutation of a conserved proline residue in the beta-subunit ectodomain prevents Na(+)-K(+)-ATPase oligomerization

1993 ◽  
Vol 265 (4) ◽  
pp. C1169-C1174 ◽  
Author(s):  
K. Geering ◽  
P. Jaunin ◽  
F. Jaisser ◽  
A. M. Merillat ◽  
J. D. Horisberger ◽  
...  
Keyword(s):  
Sodium Pump ◽  
Critical Role ◽  
Pump Current ◽  
Beta Subunit ◽  
Sequence Motif ◽  
Wild Type ◽  
Ouabain Binding ◽  
Conserved Sequence ◽  
External Potassium ◽  
And Function

A highly conserved sequence motif (4 tyrosines and 1 proline: YYPYY) of the Na(+)-K(+)-adenosinetriphosphatase (ATPase) beta 1-subunit ectodomain has been mutagenized to study its possible role in alpha/beta-assembly and sodium pump function. Single as well as double tyrosine mutants (tyrosine to phenylalanine: Y to F) of Xenopus laevis beta 1-subunits are able to associate with alpha 1-subunits and form functional Na-K pumps at the plasma membrane that are indistinguishable from wild-type alpha 1, beta 1-Na-K pumps (as assessed by measurements of ouabain binding, 86Rb flux, Na-K pump current, and activation by external potassium). In contrast, a single proline mutation (proline to glycine: P244G) reduced by > 90% the proper assembly and function of Na(+)-K(+)-ATPase, despite a normal rate of synthesis and core glycosylation. Our data indicate that proline-244 plays a critical role in the proper folding of the beta-subunit and its ability to associate efficiently with the alpha 1-subunit in the endoplasmic reticulum.

Decreased Hyperpolarization-Activated Cyclic Nucleotide-Gated Channel 2 Activity in a Rat Model of Absence Epilepsy and the Effect of ZD7288, an Ih Inhibitor, on the Spike-and-Wave Discharges

Pharmacology ◽  
2022 ◽  
pp. 1-8
Author(s):  
Melis Yavuz ◽  
Banu Aydın ◽  
Nihan Çarçak ◽  
Filiz Onat
Keyword(s):  
Rat Model ◽  
Cyclic Nucleotide ◽  
Total Duration ◽  
Absence Epilepsy ◽  
Enzyme Linked Immunosorbent Assay ◽  
Control Group ◽  
Hcn Channels ◽  
Hcn Channel ◽  
Gated Channel ◽  
Channel Currents

<b><i>Introduction:</i></b> Hyperpolarization-activated cyclic nucleotide-gated (HCN) channel currents of <i>Ih</i> and absence epilepsy seizures are associated, but studies reveal differential results. <b><i>Objective:</i></b> In our study, we aimed to investigate the role of the HCN channels on the expression of spike-and-wave discharges (SWDs) using the Genetic Absence Epilepsy Rats from Strasbourg (GAERS) model. <b><i>Methods:</i></b> HCN isoform levels from isolated brains of both naïve nonepileptic Wistar and GAERS groups were evaluated by enzyme-linked immunosorbent assay. ZD7288, an <i>Ih</i> inhibitor as well as an HCN channel antagonist, was administered intracerebroventricularly to the adult GAERS groups, and to evaluate their SWD activities, electroencephalography was recorded. The effect of ZD7288 on the cumulative total duration and number of SWDs and the mean duration of each SWD complex was evaluated. <b><i>Results:</i></b> The HCN2 levels in the cortex and hippocampus of the GAERS group were lower compared to the naïve nonepileptic Wistar group (<i>p</i> &#x3c; 0.05). ZD7288 increased the number of SWDs at the 20th and 120th min with the highest administered dose of 7 μg (<i>p</i> &#x3c; 0.05). <b><i>Conclusion:</i></b> The <i>Ih</i> inhibitor ZD7288 increased the number of SWDs in a genetic absence epilepsy rat model, although this increase may not be significant due to the inconsistent time-dependent effects. In GAERS, the cortical and hippocampal HCN2 channel levels were significantly lower compared to the control group. Further studies are needed with higher doses of ZD7288 to determine if the effects will increase drastically.

scholarly journals The eukaryotic MEP-pathway genes are evolutionarily conserved and originated from Chlaymidia and cyanobacteria

BMC Genomics ◽  
2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Liping Zeng ◽  
Katayoon Dehesh
Keyword(s):  
Phylogenetic Analyses ◽  
Single Copy ◽  
Mep Pathway ◽  
Syntenic Block ◽  
Bioinformatics Analyses ◽  
Expression Levels ◽  
Methylerythritol Phosphate ◽  
Duplication Events ◽  
History Of ◽  
The Individual

Abstract Background Isoprenoids are the most ancient and essential class of metabolites produced in all organisms, either via mevalonate (MVA)-and/or methylerythritol phosphate (MEP)-pathways. The MEP-pathway is present in all plastid-bearing organisms and most eubacteria. However, no comprehensive study reveals the origination and evolutionary characteristics of MEP-pathway genes in eukaryotes. Results Here, detailed bioinformatics analyses of the MEP-pathway provide an in-depth understanding the evolutionary history of this indispensable biochemical route, and offer a basis for the co-existence of the cytosolic MVA- and plastidial MEP-pathway in plants given the established exchange of the end products between the two isoprenoid-biosynthesis pathways. Here, phylogenetic analyses establish the contributions of both cyanobacteria and Chlamydiae sequences to the plant’s MEP-pathway genes. Moreover, Phylogenetic and inter-species syntenic block analyses demonstrate that six of the seven MEP-pathway genes have predominantly remained as single-copy in land plants in spite of multiple whole-genome duplication events (WGDs). Substitution rate and domain studies display the evolutionary conservation of these genes, reinforced by their high expression levels. Distinct phenotypic variation among plants with reduced expression levels of individual MEP-pathway genes confirm the indispensable function of each nuclear-encoded plastid-targeted MEP-pathway enzyme in plant growth and development. Conclusion Collectively, these findings reveal the polyphyletic origin and restrict conservation of MEP-pathway genes, and reinforce the potential function of the individual enzymes beyond production of the isoprenoids intermediates.

scholarly journals The MEP-pathway genes are polyphyletic origin and evolutionary conserved

2020 ◽  
Author(s):  
Liping Zeng ◽  
Katayoon Dehesh
Keyword(s):  
Phylogenetic Analyses ◽  
Single Copy ◽  
Mep Pathway ◽  
Syntenic Block ◽  
Bioinformatics Analyses ◽  
Expression Levels ◽  
Duplication Events ◽  
History Of ◽  
The Individual ◽  
Comprehensive Study

Abstract BackgroundIsoprenoids are amongst the most ancient and essential class of metabolites produced in all organisms, either via mevalonate (MVA)-and/or methylerythritol dicyclophosphate (MEP)-pathways. The MEP-pathway is present in all plastid-bearing organisms and most eubacteria. However, no comprehensive study reveals the origination and evolutionary characteristics of MEP-pathway genes in eukaryotes.ResultsHere, detailed bioinformatics analyses of the MEP-pathway provide an in-depth understanding the evolutionary history of this indispensable biochemical route, and offer a basis for the co-existence of the cytosolic MVA- and plastidial MEP-pathway in plants given the established exchange of the end products between the two isoprenoid-biosynthesis pathways. Here, phylogenetic analyses establish the contributions of both cyanobacteria and Chlamydiae sequences to the plant’s MEP-pathway genes. Moreover, Phylogenetic and inter-species syntenic block analyses demonstrate that six of the seven MEP-pathway genes have predominantly remained as single-copy in land plants in spite of multiple whole-genome duplication events (WGDs). Substitution rate and domain studies display the evolutionary conservation of these genes, reinforced by their high expression levels. Distinct phenotypic variation among plants with reduced expression levels of individual MEP-pathway genes confirm the indispensable function of each nuclear-encoded plastid-targeted MEP-pathway enzyme in plant growth and development. ConclusionCollectively, these findings reveal the polyphyletic origin and restrict conservation of MEP-pathway genes, and reinforce the potential function of the individual enzymes beyond production of the isoprenoids intermediates.

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