Publications by authors named "Jori O Ruuskanen"

18 Publications

  • Page 1 of 1

Extension of Public Smoking Ban Was Not Associated with Any Immediate Effect on Stroke Occurrence in Finland.

J Clin Med 2021 May 11;10(10). Epub 2021 May 11.

Heart Center, Turku University Hospital, 20521 Turku, Finland.

We investigated the association between the widening of a nationwide restaurant smoking ban, enacted on 1 June 2007, and stroke admissions. All acute stroke admissions between 1 May 2005 and 30 June 2009 were retrieved from a mandatory registry covering mainland Finland. Patients aged ≥18 years were included. One annual admission per patient was included. Negative binomial regression accounting for the at-risk population was applied. We found no difference in stroke occurrence before and after the smoking ban within 7 days ( = 0.217), 30 days ( = 0.176), or the whole study period ( = 0.998). Results were comparable for all stroke subtypes (ischemic stroke, intracerebral hemorrhage, and subarachnoid hemorrhage). There was no sign of decreased occurrence in June 2007 compared to June in 2005-2006, and all subtypes of stroke occurred at least as frequently in both May and June of 2008 as in May and June of 2007. In conclusion, the nationwide restaurant smoking ban Finland enacted in June 2007 was not associated with any immediate reduction in stroke occurrence.
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http://dx.doi.org/10.3390/jcm10102060DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8151542PMC
May 2021

Case fatality of hospital-treated intracerebral hemorrhage in Finland - A nationwide population-based registry study.

J Neurol Sci 2021 06 14;425:117446. Epub 2021 Apr 14.

Heart Center, Turku University Hospital, Turku, Finland; Research Center of Applied and Preventive Cardiovascular Medicine, University of Turku, Turku, Finland; Center for Population Health Research, Turku University Hospital and University of Turku, Turku, Finland; Administrative Center, Hospital District of Southwest Finland, Turku, Finland. Electronic address:

Background: Case-fatality of Intracerebral hemorrhage (ICH) has been reported to have improved in some areas recently. Previous reports have shown that in Finland ICH survival has improved already from the 1980s. We aimed to investigate if this trend has continued and to assess possible predictors for death.

Methods: All patients hospitalized for ICH in Finland in 2004-2018 over 16 years of age were identified from a national registry. Survival was analyzed using the national causes of death registry with median follow-up of 5.1 years (max 15.0 years).

Results: 20,391 persons with ICH (53.5% men) were identified. Patient age increased during the study period with men being younger than women. One-month case-fatality was 28.4% and decreased during the study period. One-month and long-term case-fatality increased with patient age. Five-year survival was over 64% in patients <65 years of age and < 33% in those >75 years of age. In a multivariate analysis patient age, sex, comorbidity burden and diagnoses of atrial fibrillation, hypertension and coagulopathy were all independently associated with both 30-day and long-term survival. Survival was better in men than women at all time points but in the multivariate analysis male sex was associated with a slightly higher risk (hazard ratio 1.10, 95% CI 1.06-1.14) of death in the long-term follow-up. Compared to general population, excess case-fatality was high and highly age-dependent in both sexes.

Conclusions: Case-fatality of hospital-treated ICH has continued to decrease in Finland. Prognosis is strongly associated with patient age and more modestly with patient sex and comorbidities.
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http://dx.doi.org/10.1016/j.jns.2021.117446DOI Listing
June 2021

Cerebral Venous Thrombosis: Finnish Nationwide Trends.

Stroke 2021 01 4;52(1):335-338. Epub 2020 Dec 4.

Neurocenter, Department of Neurology, Clinical Neurosciences (J.O.R., J.O.T.S.), University of Turku, Finland.

Background And Purpose: Epidemiology of cerebral venous thrombosis (CVT) has been reported to be changing. Because long-term nationwide data are needed to confirm this, we studied CVT occurrence between 2005 and 2014 in Finland.

Methods: All acute CVT admissions were retrieved from a mandatory registry covering mainland Finland. Patients aged ≥18 years were included. One admission per patient was allowed.

Results: We identified 563 patients with CVT (56.5% women). Overall incidence was 1.32/100 000 (95% CI, 1.21-1.43) per year with a 5.0% annual increase. In people <55 years of age, incidence was 0.92/100 000 (0.76-1.10) for men and 1.65/100 000 (1.43-1.89) for women, whereas for those 55 years or older incidence was 1.61 (1.34-1.91) for men and 1.17 (0.96-1.41) for women. In-hospital mortality was 2.1% with no sex difference. One-year mortality was 7.9%. Long-term mortality was higher in men (adjusted hazard ratio, 1.61 [1.09-2.38]) and in older patients (1.95 [1.69-2.24]; per 10-year increment).

Conclusions: Overall incidence of CVT in Finland was similar to that reported in the Netherlands and in Australia. There was a 5.0% yearly increase in the rate of admissions while in-hospital mortality was low. Sex-specific incidence rates differed markedly between younger and older people. Long-term mortality increased with age and was higher in men.
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http://dx.doi.org/10.1161/STROKEAHA.120.031026DOI Listing
January 2021

Adult Migraine Hospital Admission Trends in Finland: A Nationwide Registry Study.

J Clin Med 2020 Jan 23;9(2). Epub 2020 Jan 23.

Heart Center, Turku University Hospital, 20521 Turku, Finland.

Population-level data on migraine hospital admission trends are unavailable. Changes in stroke care may have influenced these, since migraine is one of the most common stroke mimics. In this study, all hospital admissions on neurological, internal medicine, and pediatric wards in Finland with migraine as the primary diagnosis for persons at least 16 years of age in 2004-2014 were studied, resulting in an analysis of 6195 individuals with 7764 migraine discharges. The number of discharges increased by 4.2% annually ( = 0.000084), with no change in age of the admitted patients. Comorbidity burden was low but increased during the study period ( < 0.0001). The frequency of common vascular risk factors as comorbidities increased by 11-19% annually. Admission duration shortened by 2% annually ( < 0.0001). An intravenous thrombolysis was given in four admissions. It seems that migraine hospital admissions have become more frequent and the patients more often have cardiovascular risk factors, suggesting increased awareness and more aggressive acute evaluation of suspected stroke as the cause.
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http://dx.doi.org/10.3390/jcm9020320DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7073942PMC
January 2020

Fatal traumatic brain injuries during 13 years of successive alcohol tax increases in Finland - a nationwide population-based registry study.

Sci Rep 2019 04 1;9(1):5419. Epub 2019 Apr 1.

Heart Center, Turku University Hospital, Turku, Finland.

We sought to investigate how increases in alcohol taxation and changes in alcohol consumption were associated with the incidence rate of fatal traumatic brain injuries (TBI) in Finland during the years 2004-2016. Nationwide, mandatory cause of death database covering all deaths in Finland was searched for all deaths related to TBIs (ICD-10: S06.X) in persons ≥16 years of age during 2004-2016. Study period included 28,657,870 person-years and 325,514 deaths of which 12,110 were TBI-related. Occurrence rates were standardized to European 2013 standard population. Data for alcohol consumption were obtained from the National Institute for Health and Welfare and for alcohol taxation from Ministry of Finance, Finland. Standardized incidence rate of TBI-related death was 22.0 (95% CI 21.61-22.38) per 100,000 person-years. Overall alcohol consumption decreased on average by 1.2% annually. Concurrently, the overall incidence rate of fatal TBIs decreased by 4.1% annually (by 4.3% in men and 2.4% in women). There was an association between overall alcohol consumption and TBI-related mortality rate (p < 0.001). Tax-rate increases of all beverage types were associated with decreased incidence rate of TBI-related death in men (p < 0.001), in women (p < 0.036) and overall (p < 0.001). In this population-based study, we report that during 13 years of successive alcohol tax increases, overall alcohol consumption has decreased in parallel with a reduction in the incidence rate of fatal TBIs in Finland.
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http://dx.doi.org/10.1038/s41598-019-41913-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6443785PMC
April 2019

Stroke hospitalization trends of the working-aged in Finland.

PLoS One 2018 1;13(8):e0201633. Epub 2018 Aug 1.

Heart Center, Turku University Hospital, Turku, Finland.

Background: The age-standardized incidence of stroke has decreased globally but, for reasons unknown, conflicting results have been observed regarding trend in incidence of major stroke subtypes in young adults. We studied these trends among people of working age in a population-based setting in Finland, where cardiovascular risk factor profiles have developed favorably.

Methods: All hospitalizations for stroke in 2004-2005 and 2013-2014 for persons 18-64 years of age were identified from a national register. The search included all hospitals that provide acute stroke care on mainland Finland.

Results: Hospitalizations for both intracerebral hemorrhage (ICH; -15.2%; p = 0.0008) and subarachnoid hemorrhage (SAH; -26.5%; p<0.0001) decreased overall and for both sexes separately. Concerning IS, hospitalizations decreased only for men (-6.3%; p = 0.0190) but not for women or overall. However, there was an increase in IS hospitalizations in men 35-44 years of age (+37.5%; p = 0.0019). The length of stay (LOS) of IS patients declined in nearly all subgroups (overall -20.8%, p<0.0001) whereas no change in LOS was observed for patients with ICH or SAH. In-hospital mortality decreased in patients with IS (-42.8%; p = 0.0092) but remained unchanged in patients with ICH or SAH.

Conclusions: Stroke hospitalizations of young people declined in Finland, except for men 35-44 years of age for whom IS hospitalizations increased. Declining LOS and in-hospital mortality of IS patients suggests admission of less severe cases, improved care or both.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0201633PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6070270PMC
February 2019

No association of moon phase with stroke occurrence.

Chronobiol Int 2018 08 23;35(8):1168-1174. Epub 2018 May 23.

f Research Centre of Applied and Preventive Cardiovascular Medicine , University of Turku , Turku , Finland.

Stroke occurrence shows strong correlations with sleep disorders and even subtle sleep disturbances have been shown to affect ischemic stroke (IS) occurrence. Chronobiology also exerts effects, like the morning surge in IS occurrence. Lunar cycles have also been shown to affect sleep and other physiological processes, but studies on moon phases and its possible association with occurrence of stroke are rare and nonconclusive. Therefore, we studied the effects of moon phases on stroke hospitalizations and in-hospital mortality nationwide in Finland in 2004-2014. All patients aged ≥18 years with IS or intracerebral hemorrhage (ICH) as primary discharge diagnosis were included. Daily number of admissions was treated as a response variable while moon phase, year and astronomical season were independent variables in Poisson regression modeling. We found no association between moon phases and stroke occurrence. The overall occurrence rates did not vary between different moon phases for IS or ICH (p = 0.61 or higher). There were no differences between moon phases in daily admission rates among men, women, young and old patients for any of the stroke subtypes. There was no difference in in-hospital mortality with regard to moon phase for IS or ICH overall (p = 0.19 or higher), nor in subgroup analyses. There were no significant interactions between moon phase and astronomical season for stroke occurrence or in-hospital mortality. To conclude, in this over a decade-long nationwide study including a total of 46 million person years of follow-up, we found no association between moon phases and occurrence or in-hospital mortality rates of IS or intracerebral hemorrhage.
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http://dx.doi.org/10.1080/07420528.2018.1465071DOI Listing
August 2018

Epidemiology of Guillain-Barré syndrome in Finland 2004-2014.

J Peripher Nerv Syst 2017 12 15;22(4):440-445. Epub 2017 Nov 15.

Heart Center, Turku University Hospital, Turku, Finland.

At total mean incidence of 0.84-1.1/100,000 the occurrence of Guillain-Barré syndrome (GBS) is reported to be low in Finland compared to other Caucasian populations. However, a recent study from Southwestern Finland reported an incidence of 1.82/100,000 which is comparable to other Caucasian populations. We analyzed discharge data covering the years 2004 through 2014 on all neurological admissions in all Finnish university and central hospitals with a primary diagnosis of GBS. A total of 989 admissions due to GBS (917 individuals) were identified. The standardized (European population) annual incidence rate was 1.70/100,000 person-years (95% confidence interval 1.60-1.81). GBS incidence had an increasing trend with age. The likelihood of GBS was higher among girls and adolescent women than boys and men of same age (male:female incidence rate ratio [IRR] 0.56), while in the older age groups (>19 years) the occurrence of GBS was higher among males than females (male:female IRR 1.59). The incidence of GBS remained stable during the study period. There was no seasonal variation in GBS admission frequencies (p = 0.28). No significant effect of the 2009-2010 H1N1 influenza or vaccination against it for GBS occurrence was observed. We suggest that GBS is as common, and has similar age-distribution in Finland as in other European countries. Sex-associated susceptibility for GBS appears to be different in children-adolescents and adults.
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http://dx.doi.org/10.1111/jns.12239DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5765466PMC
December 2017

Changes in ischemic stroke occurrence following daylight saving time transitions.

Sleep Med 2016 Nov - Dec;27-28:20-24. Epub 2016 Nov 2.

Research Centre of Applied and Preventive Cardiovascular Medicine, University of Turku, Turku, Finland; Heart Center, Turku University Hospital, Turku, Finland.

Background: Circadian rhythm disruption has been associated with increased risk of ischemic stroke (IS). Daylight saving time (DST) transitions disrupt circadian rhythms and shifts the pattern of diurnal variation in stroke onset, but effects on the incidence of IS are unknown.

Methods: Effects of 2004-2013 DST transitions on IS hospitalizations and in-hospital mortality were studied nationwide in Finland. Hospitalizations during the week following DST transition (study group, n = 3033) were compared to expected hospitalizations (control group, n = 11,801), calculated as the mean occurrence during two weeks prior to and two weeks after the index week.

Results: Hospitalizations for IS increased during the first two days (Relative Risk 1.08; CI 1.01-1.15, P = 0.020) after transition, but difference was diluted when observing the whole week (RR 1.03; 0.99-1.06; P = 0.069). Weekday-specific increase was observed on the second day (Monday; RR 1.09; CI 1.00-1.90; P = 0.023) and fifth day (Thursday; RR 1.11; CI 1.01-1.21; P = 0.016) after transition. Women were more susceptible than men to temporal changes during the week after DST transitions. Advanced age (>65 years) (RR 1.20; CI 1.04-1.38; P = 0.020) was associated with increased risk during the first two days, and malignancy (RR 1.25; CI 1.00-1.56; P = 0.047) during the week after DST transition.

Conclusions: DST transitions appear to be associated with an increase in IS hospitalizations during the first two days after transitions but not during the entire following week. Susceptibility to effects of DST transitions on occurrence of ischemic stroke may be modulated by gender, age and malignant comorbidities.
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http://dx.doi.org/10.1016/j.sleep.2016.10.009DOI Listing
February 2018

Seasonality of stroke in Finland.

Ann Med 2017 06 29;49(4):310-318. Epub 2016 Nov 29.

i Heart Center, Turku University Hospital , Turku , Finland.

Introduction: The burden of stroke is increasing globally. Reports on seasonal variations in stroke occurrence are conflicting and long-term data are absent.

Methods: A retrospective cohort study using discharge registry data of all acute stroke admissions in Finland during 2004-2014 for patients ≥18 years age. A total of 97,018 admissions for ischemic stroke (IS) were included, 18,252 admissions for intracerebral hemorrhage (ICH) and 11,271 admissions for subarachnoid hemorrhage (SAH).

Results: The rate of IS admissions increased (p = 0.025) while SAH admission rate decreased (p < 0.0001), and ICH admission rate remained stable during the study period. The lowest seasonal admission rates were detected in summer and the highest in autumn for all stroke subtypes. Seasonal variation of IS was more pronounced in men (p = 0.020), while no sex difference was detected in ICH or SAH. The seasonal patterns of in-hospital mortality and length of stay (LOS) differed markedly by stroke subtype. Diagnoses of hypertension, atrial fibrillation, or diabetes showed no seasonality.

Conclusions: All major stroke subtypes occurred most commonly in autumn and most infrequently in summer. Seasonality of in-hospital mortality and length of hospital stay appears to vary by stroke subtype. The seasonal pattern of ischemic stroke occurrence appears to have changed during the past decades. Key messages All major stroke subtypes (ischemic stroke, intracerebral hemorrhage, subarachnoid hemorrhage) occurred most frequently in autumn and least frequently in summer. Seasonal patterns of in-hospital mortality and length of stay differed markedly by stroke subtype. The seasonal pattern of ischemic stroke occurrence in Finland seems to have changed compared to 1982-1992.
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http://dx.doi.org/10.1080/07853890.2016.1254350DOI Listing
June 2017

Effect of the summer holiday season on ischaemic stroke care in Finland.

J Neurol Sci 2016 Aug 23;367:363-4. Epub 2016 Jun 23.

Heart Center, Turku University Hospital, Turku, Finland, and Research Center of Applied and Preventive Cardiovascular Medicine, University of Turku, Turku, Finland.

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http://dx.doi.org/10.1016/j.jns.2016.06.047DOI Listing
August 2016

Early pregnancy cerebral venous thrombosis and status epilepticus treated with levetiracetam and lacosamide throughout pregnancy.

Reprod Toxicol 2015 Nov 14;57:204-6. Epub 2015 Jul 14.

Institute of Clinical Medicine, Department of Neurology, University of Turku, Turku, Finland; Division of Clinical Neurosciences, Turku University Hospital, Turku, Finland; Medbase Ltd., Turku, Finland. Electronic address:

Cerebral venous thrombosis (CVT) is an uncommon cause of stroke, accounting to less than 1% of all strokes. We describe a pregnant woman with a massive CVT in early pregnancy, complicated by status epilepticus. The mother was treated with levetiracetam, lacosamide, and enoxaparin throughout pregnancy. A male infant was born on pregnancy week 36, weighing 2.2kg. Both levetiracetam and and lacosamide were present in cord blood in levels similar to those in maternal blood. The infant was partially breast-fed and experienced poor feeding and sleepiness, starting to resolve after two first weeks. Milk samples were drawn 5 days after the delivery and a blood sample from the infant 3 days later. Lacosamide level in milk was low, resulting in an estimated relative infant dose of 1.8% of the maternal weight-adjusted daily dose in a fully breast-fed infant. This is the first case describing lacosamide use during pregnancy and lactation.
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http://dx.doi.org/10.1016/j.reprotox.2015.07.068DOI Listing
November 2015

Differential expression of dopaminergic cell markers in the adult zebrafish forebrain.

J Comp Neurol 2011 Feb;519(3):576-98

Neurobiology & Development (UPR3294), Institute of Neurobiology Alfred Fessard, Centre National de la Recherche Scientifique, 91198 CNRS Gif-sur-Yvette, France.

Although the simultaneous presence of tyrosine hydroxylase (TH), aromatic amino acid decarboxylase (AADC), dopamine transporter (DAT), and vesicular monoamine transporter 2 (VMAT2) is considered as a phenotypic signature of dopamine (DA) neurons, it has been suggested that they are not uniformly expressed in all dopaminergic brain nuclei. Moreover, in nonmammalian vertebrates, two tyrosine hydroxylase genes (TH1 and TH2) are found, and they exhibit different expression patterns in zebrafish brains. Here we present a detailed description of the distribution of TH1, TH2, AADC, DAT, and VMAT2 transcripts, in relation to TH and DA immunoreactivity to better characterize dopaminergic nuclei in the adult zebrafish forebrain. TH2-positive cells in the hypothalamus are strongly DA immunoreactive (DAir), providing direct evidence that they are dopaminergic. DAir cells are also found in most TH1-positive or TH-immunoreactive (THir) nuclei. However, the DAir signal was weaker than THir in the olfactory bulb, telencephalon, ventral thalamus, pretectum, and some posterior tubercular and preoptic nuclei. These cell populations also exhibited low levels of VMAT2 transcripts, suggesting that low DA is due to a lower vesicular DA accumulation. In contrast, cell populations with low levels of AADC did not always have low levels of DA. DAT transcripts were abundantly expressed in most of the TH1- or TH2-positive territories. In addition, DAT and/or VMAT2 transcripts were found in some periventricular cell populations such as in the telencephalon without TH1 or TH2 expression. Thus, expression patterns of dopaminergic cell markers are not homogeneous, suggesting that the gene regulatory logic determining the dopaminergic phenotype is unexpectedly complex.
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http://dx.doi.org/10.1002/cne.22535DOI Listing
February 2011

Two tyrosine hydroxylase genes in vertebrates New dopaminergic territories revealed in the zebrafish brain.

Mol Cell Neurosci 2010 Apr 1;43(4):394-402. Epub 2010 Feb 1.

Développement, Evolution, Plasticité du Système Nerveux, Institut de Neurobiologie Alfred Fessard, CNRS Gif-sur-Yvette, France.

Tyrosine hydroxylase (TH) is the rate limiting enzyme for dopamine synthesis, catalyzing transformation of l-tyrosine to l-DOPA. Two TH genes (TH1 and TH2) have been reported to exist in the genome of some teleost fishes, TH1 being orthologous to the mammalian TH gene (Candy and Collet, 2005). Here we show that two TH genes are commonly found in genomes of jawed vertebrates. Our analyses of molecular phylogeny and gene synteny strongly suggest that the two TH genes emerged as a consequence of a whole genome duplication before the divergence of jawed vertebrates, and that TH2 was secondarily lost in eutherians (placental mammals). The distribution of TH1 and TH2 transcripts revealed that TH1 and TH2 are differentially expressed in the zebrafish adult brain, as often observed for duplicated genes. In particular we found that TH2 transcripts were much more abundant than TH1 in the hypothalamus, and that the TH2 cells along the periventricular zone are devoid of TH immunoreactivity, due to the lack of affinity of the available anti-TH antibodies. Although these neurons have been considered to be dopamine-uptaking cells in previous studies, the expression of other monoaminergic markers such as aromatic amino acid decarboxylase (AADC), dopamine transporter (DAT), and vesicular monoamine transporter 2 (VMAT2) suggests that these TH2 cells are dopamine-synthesizing neurons.
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http://dx.doi.org/10.1016/j.mcn.2010.01.006DOI Listing
April 2010

Expression and function of alpha-adrenoceptors in zebrafish: drug effects, mRNA and receptor distributions.

J Neurochem 2005 Sep 5;94(6):1559-69. Epub 2005 Jul 5.

Department of Pharmacology and Clinical Pharmacology, University of Turku, Turku, Finland.

The alpha2-adrenoceptors are G-protein-coupled receptors that mediate many of the physiological effects of norepinephrine and epinephrine. Mammals have three subtypes of alpha2-adrenoceptors, alpha2A, alpha2B and alpha2C. Zebrafish, a teleost fish used widely as a model organism, has five distinct alpha2-adrenoceptor genes. The zebrafish has emerged as a powerful tool to study development and genetics, with many mutations causing diseases reminiscent of human diseases. Three of the zebrafish adra2 genes code for orthologues of the mammalian alpha2-adrenoceptors, while two genes code for alpha2Da- and alpha2Db- adrenoceptors, representing a duplicated, fourth alpha2-adrenoceptor subtype. The three different mammalian alpha2-adrenoceptor subtypes have distinct expression patterns in different organs and tissues, and mediate different physiological functions. The zebrafish alpha2-adrenergic system, with five different alpha2-adrenoceptors, appears more complicated. In order to deduce the physiological functions of the zebrafish alpha2-adrenoceptors, we localized the expression of the five different alpha2-adrenoceptor subtypes using RT-PCR, mRNA in situ hybridization, and receptor autoradiography using the radiolabelled alpha2-adrenoceptor antagonist [ethyl-3H]RS-79948-197. Localization of the alpha2A-, alpha2B- and alpha2C-adrenoceptors in zebrafish shows marked conservation when compared with mammals. The zebrafish alpha2A, alpha2Da, and alpha2Db each partially follow the distribution pattern of the mammalian alpha2A: a possible indication of subfunction partitioning between these subtypes. The alpha2-adrenergic system is functional in zebrafish also in vivo, as demonstrated by marked locomotor inhibition, similarly to mammals, and lightening of skin colour induced by the specific alpha2-adrenoceptor agonist, dexmedetomidine. Both effects were antagonized by the specific alpha2-adrenoceptor antagonist atipamezole.
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http://dx.doi.org/10.1111/j.1471-4159.2005.03305.xDOI Listing
September 2005

Model structures of alpha-2 adrenoceptors in complex with automatically docked antagonist ligands raise the possibility of interactions dissimilar from agonist ligands.

J Struct Biol 2005 May;150(2):126-43

Department of Biochemistry and Pharmacy, Abo Akademi University, Tykistökatu 6 A, FIN-20520 Turku, Finland.

Antagonist binding to alpha-2 adrenoceptors (alpha2-ARs) is not well understood. Structural models were constructed for the three human alpha2-AR subtypes based on the bovine rhodopsin X-ray structure. Twelve antagonist ligands (including covalently binding phenoxybenzamine) were automatically docked to the models. A hallmark of agonist binding is the electrostatic interaction between a positive charge on the agonist and the negatively charged side chain of D3.32. For antagonist binding, ion-pair formation would require deviations of the models from the rhodopsin structural template, e.g., a rotation of TM3 to relocate D3.32 more centrally within the binding cavity, and/or creation of new space near TM2/TM7 such that antagonists would be shifted away from TM5. Thus, except for the quinazolines, antagonist ligands automatically docked to the model structures did not form ion-pairs with D3.32. This binding mode represents a valid alternative, whereby the positive charge on the antagonists is stabilized by cation-pi interactions with aromatic residues (e.g., F6.51) and antagonists interact with D3.32 via carboxylate-aromatic interactions. This binding mode is in good agreement with maps derived from a molecular interaction library that predicts favorable atomic contacts; similar interaction environments are seen for unrelated proteins in complex with ligands sharing similarities with the alpha2-AR antagonists.
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http://dx.doi.org/10.1016/j.jsb.2004.12.008DOI Listing
May 2005

Conserved structural, pharmacological and functional properties among the three human and five zebrafish alpha 2-adrenoceptors.

Br J Pharmacol 2005 Jan;144(2):165-77

Department of Pharmacology and Clinical Pharmacology, University of Turku, Itäinen Pitkäkatu 4 B, Turku FI-20520, Finland.

1. Zebrafish has five distinct alpha(2)-adrenoceptors. Two of these, alpha(2Da) and alpha(2Db), represent a duplicated, fourth alpha(2)-adrenoceptor subtype, while the others are orthologue of the human alpha(2A)-, alpha(2B)- and alpha(2C)-adrenoceptors. Here, we have compared the pharmacological properties of these receptors to infer structural determinants of ligand interactions. 2. The zebrafish alpha(2)-adrenoceptors were expressed in Chinese hamster ovary cells and tested in competitive ligand binding assays and in a functional assay (agonist-stimulated [(35)S]GTPgammaS binding). The affinity results were used to cluster the receptors and, separately, the ligands using both principal component analysis and binary trees. 3. The overall ligand binding characteristics, the order of potency and efficacy of the tested agonists and the G-protein coupling of the zebrafish and human alpha(2)-adrenoceptors, separated by approximately 350 million years of evolution, were found to be highly conserved. The binding affinities of the 20 tested ligands towards the zebrafish alpha(2)-adrenoceptors are generally comparable to those of their human counterparts, with a few compounds showing up to 40-fold affinity differences. 4. The alpha(2A) orthologues and the zebrafish alpha(2D) duplicates clustered as close pairs, but the relationships between the orthologues of alpha(2B) and alpha(2C) were not clearly defined. Applied to the ligands, our clustering methods segregated the ligands based on their chemical structures and functional properties. As the ligand binding pockets formed by the transmembrane helices show only minor differences among the alpha(2)-adrenoceptors, we suggest that the second extracellular loop--where significant sequence variability is located --might contribute significantly to the observed affinity differences.
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http://dx.doi.org/10.1038/sj.bjp.0706057DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1575993PMC
January 2005

Identification of duplicated fourth alpha2-adrenergic receptor subtype by cloning and mapping of five receptor genes in zebrafish.

Mol Biol Evol 2004 Jan 29;21(1):14-28. Epub 2003 Aug 29.

Department of Pharmacology and Clinical Pharmacology, Turku Graduate School of Biomedical Sciences, University of Turku, Finland.

The alpha(2)-adrenergic receptors (alpha(2)-ARs) belong to the large family of rhodopsinlike G-protein-coupled receptors that share a common structure of seven transmembrane (TM) alpha-helices. The aims of this study were (1) to determine the number of alpha(2)-AR genes in a teleost fish, the zebrafish (Danio rerio), (2) to study the gene duplication events that generated the alpha(2)-AR subtypes, and (3) to study changes in receptor structure that have occurred since the divergence of the mammalian and fish lineages. Here, we report the cloning and chromosomal mapping of fish orthologs for all three mammalian alpha(2)-ARs. In addition, we identified a fourth alpha(2)-AR subtype with two duplicates in zebrafish. Chromosomal mapping showed that the zebrafish alpha(2)-AR genes are located within conserved chromosomal segments, consistent with the origin of the four alpha(2)-AR subtypes by two rounds of chromosome or block duplication before the divergence of the ray fin fish and tetrapod lineages. Thus, the fourth subtype has apparently been present in the common ancestor of vertebrates but has been deleted or is yet to be identified in mammals. The overall percentage identity between the fish and mammalian orthologs is 53% to 67%, and in the TM regions 80% to 87%. These values are clearly lower than what is observed between mammalian orthologs. Still, all of the residues thought to be important for alpha(2)-adrenergic ligand binding are conserved across species and subtypes, and even the most divergent regions of the fish receptors show clear "molecular fingerprints" typical for orthologs of a given subtype.
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http://dx.doi.org/10.1093/molbev/msg224DOI Listing
January 2004