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Biomedical subjects

S Wilhelm

Publications and source records attributed to S Wilhelm.

At least 37 records · Page 2Linked to original sources
PubMed2002

Acute normovolaemic haemodilution beyond a haematocrit of 25%: ratio of skeletal muscle tissue oxygen tension and cardiac index is not maintained in the healthy dog.

BACKGROUND AND OBJECTIVE: The study investigated the effect of acute normovolaemic haemodilution on haemodynamics, blood flow and oxygen transport variables with regard to skeletal muscle tissue oxygenation in a canine model. METHODS: Twenty foxhounds were anaesthetized, mechanically ventilated with 30% oxygen in air and underwent first-step normovolaemic haemodilution with Ringer's lactate solution to haematocrit (Hct) 30 and 25% and second-step acute normovolaemic haemodilution with 6% Hetastarch 70,000/0.5 to Hcts of 20, 15 and 10%. Catheters were inserted into femoral arteries and veins and into the pulmonary artery for measurements ofhaemodynamics, temperature, and sampling of arterial and mixed-venous blood. A flow probe was placed around the left femoral artery. Skeletal muscle tissue oxygen tension (tPO2) was measured in the gastrocnemius muscle using a stepwise driven polarographic needle probe creating histograms from 200 single tPO2 measurements. RESULTS: Until a Hct of 25% was reached, the heart rate, mean arterial pressure, global and muscular oxygen delivery and consumption remained constant, while the cardiac index and oxygen extraction ratio were significantly increased when compared with baseline. The median tPO2 was significantly decreased at Hcts 15 and 10%, despite increased cardiac index and regional blood flow. The ratio of tPO2 and cardiac index as a marker for efficiency of acute normovolaemic haemodilution started to decline beyond Hcts of 25% (change of slope). CONCLUSIONS: In acute normovolaemic haemodilution to the level of Hct of 25%, the ratio between tPO2 and cardiac index decreases in the healthy dog, indicating an uneconomic relation at the threshold of Hct of 25%.

Analysis of Variance↗
PubMed2002

Regulation of AE2-mediated Cl- transport by intracellular or by extracellular pH requires highly conserved amino acid residues of the AE2 NH2-terminal cytoplasmic domain.

We reported recently that regulation by intracellular pH (pH(i)) of the murine Cl-/HCO(3)(-) exchanger AE2 requires amino acid residues 310-347 of the polypeptide's NH(2)-terminal cytoplasmic domain. We have now identified individual amino acid residues within this region whose integrity is required for regulation of AE2 by pH. 36Cl- efflux from AE2-expressing Xenopus oocytes was monitored during variation of extracellular pH (pH(o)) with unclamped or clamped pH(i), or during variation of pH(i) at constant pH(o). Wild-type AE2-mediated 36Cl- efflux was profoundly inhibited by acid pH(o), with a value of pH(o50) = 6.87 +/- 0.05, and was stimulated up to 10-fold by the intracellular alkalinization produced by bath removal of the preequilibrated weak acid, butyrate. Systematic hexa-alanine [(A)6]bloc substitutions between aa 312-347 identified the greatest acid shift in pH(o(50)) value, approximately 0.8 pH units in the mutant (A)6 342-347, but only a modest acid-shift in the mutant (A)6 336-341. Two of the six (A)6 mutants retained normal pH(i) sensitivity of 36Cl- efflux, whereas the (A)6 mutants 318-323, 336-341, and 342-347 were not stimulated by intracellular alkalinization. We further evaluated the highly conserved region between aa 336-347 by alanine scan and other mutagenesis of single residues. Significant changes in AE2 sensitivity to pH(o) and to pH(i) were found independently and in concert. The E346A mutation acid-shifted the pH(o(0) value to the same extent whether pH(i) was unclamped or held constant during variation of pH(o). Alanine substitution of the corresponding glutamate residues in the cytoplasmic domains of related AE anion exchanger polypeptides confirmed the general importance of these residues in regulation of anion exchange by pH. Conserved, individual amino acid residues of the AE2 cytoplasmic domain contribute to independent regulation of anion exchange activity by pH(o) as well as pH(i).

Acids↗
PubMed2002

Neuroprotective and neurotoxic properties of the 'inert' gas, xenon.

BACKGROUND: Antagonists of the N-methyl-D-aspartate (NMDA) subtype of glutamate receptors have been shown not only to have neuroprotective effects but also to exhibit neurotoxic properties. In this study, we used c-Fos, a protein product of an immediate early gene, as a marker of neuronal injury to compare the neuroprotective effects of xenon and the neurotoxic properties of xenon, nitrous oxide, and ketamine, three anaesthetics with NMDA receptor antagonist properties. METHODS: We used an in vivo rat model of brain injury in which N-methyl-DL-aspartic acid (NMA) is injected subcutaneously (s.c.) and c-Fos expression in the arcuate nucleus is used as a measure of injury. To examine the neurotoxic potential of each of the three anaesthetics with NMDA receptor antagonist properties, c-Fos expression in the posterior cingulate and retrosplenial (PC/RS) cortices was measured. RESULTS: Xenon dose-dependently suppressed NMA-induced c-Fos expression in the arcuate nucleus with an IC(50) of 47 (2)% atm. At the highest concentration tested (75% atm) NMA-induced neuronal injury was decreased by as much as that observed with the prototypical NMDA antagonist MK801 (0.5 mg kg(-1) s.c.). Both nitrous oxide and ketamine dose-dependently increased c-Fos expression in PC/RS cortices; in contrast, xenon produced no significant effect. If the dopamine receptor antagonist haloperidol was given before either nitrous oxide or ketamine, their neurotoxic effects were eliminated. CONCLUSIONS: Uniquely amongst anaesthetics with known NMDA receptor antagonist action, xenon exhibits neuroprotective properties without co-existing neurotoxicity. The reason why ketamine and nitrous oxide, but not xenon, produce neurotoxicity may involve their actions on dopaminergic pathways.

Animals↗
PubMed2001

A dominant negative mutant of the KCC1 K-Cl cotransporter: both N- and C-terminal cytoplasmic domains are required for K-Cl cotransport activity.

K-Cl cotransport regulates cell volume and chloride equilibrium potential. Inhibition of erythroid K-Cl cotransport has emerged as an important adjunct strategy for the treatment of sickle cell anemia. However, structure-function relationships among the polypeptide products of the four K-Cl cotransporter (KCC) genes are little understood. We have investigated the importance of the N- and C-terminal cytoplasmic domains of mouse KCC1 to its K-Cl cotransport function expressed in Xenopus oocytes. Truncation of as few as eight C-terminal amino acids (aa) abolished function despite continued polypeptide accumulation and surface expression. These C-terminal loss-of-function mutants lacked a dominant negative phenotype. Truncation of the N-terminal 46 aa diminished function. Removal of 89 or 117 aa (Delta(N)117) abolished function despite continued polypeptide accumulation and surface expression and exhibited dominant negative phenotypes that required the presence of the C-terminal cytoplasmic domain. The dominant negative loss-of-function mutant Delta(N)117 was co-immunoprecipitated with wild type KCC1 polypeptide, and its co-expression did not reduce wild type KCC1 at the oocyte surface. Delta(N)117 also exhibited dominant negative inhibition of human KCC1 and KCC3 and, with lower potency, mouse KCC4 and rat KCC2.

Animals↗
PubMed2001

Structure and complex transcription pattern of the mouse SK1 K(Ca) channel gene, KCNN1.

Small conductance calcium-gated K(+) channels (SK channels) are encoded by the three SK genes, SK1, SK2, and SK3. These channels likely contribute to slow synaptic afterhyperpolarizations of apamin-sensitive and apamin-insensitive types. SK channels are also widely expressed outside the nervous system. The mouse SK1 gene comprises at least 12 exons extending across 19.8 kb of genomic DNA. This gene encodes a complex pattern of alternatively spliced SK1 transcripts widely expressed among mouse tissues. These transcripts exhibit at least four distinct 5'-nucleotide sequence variants encoding at least two N-terminal amino acid sequences. Optional inclusion of exons 7 and 9, together with two alternate splice donor sites in exon 8, yields transcripts encoding eight variant C-terminal amino acid sequences for SK1. These include an altered putative S6 transmembrane span, modification of the C-terminal cytoplasmic domain binding site for calmodulin, and generation of two alternate predicted binding sites for PDZ domain-containing proteins. 20 of the 32 predicted mouse SK1 transcripts are expressed in brain at levels sufficient to allow consistent detection, and encode 16 SK1 polypeptide variants. Only four of these 16 polypeptides preserve the ability to bind calmodulin in a Ca(2+)-independent manner. Mouse SK1 also exhibits novel, strain-specific, length polymorphism of a polyglutamate repeat in the N-terminal cytoplasmic domain. The evolutionary conservation of this complex transcription pattern suggests a possible role in the tuning of SK1 channel function.

3' Untranslated Regions↗
PubMed2001

High-dose etoposide phosphate and G-CSF mobilizes peripheral blood stem cells in patients that previously failed to mobilize.

Ten consecutive patients in our unit who had failed to mobilize a sufficient stem cell yield after either an initial or several mobilization regimens received high-dose etoposide phosphate (1500-2000 mg/m2) followed by granulocyte colony-stimulating factor (G-CSF; 10 micrograms/kg per day) to stimulate mobilization. Eight of the ten patients were apheresed. A median of 2.1 x 10(6) CD34+/kg (range 0-5.2) was collected. The number of CD34+ cells/microliter peripheral blood (pB) was significantly increased compared to the first-line mobilization [median 13.0 (range 2.68-29) versus median 4.76 (range 1.36-12); P < 0.05]. Besides hematotoxicity and four cases of infection (WHO grade 3), no major side effects were seen. The median duration of neutropenia was short (5 days, range 0-10), which is important in heavily pretreated patients. These results indicate that high-dose etoposide phosphate with G-CSF is safe, well tolerated, and may be effective in peripheral blood stem cell (PBSC) mobilization in patients who had previously failed to mobilize.

Adult↗
PubMed2001

Pneumoperitoneum upregulates preproendothelin-1 messenger RNA.

BACKGROUND: Laparoscopic pneumoperitoneum has been shown to decrease glomerular filtration rate (GFR) and urine volume (UV). Endothelin-1 (ET-1), a potent renal vasoconstrictor, has been implicated. The purpose of this study was to determine renal function, ET-1 gene expression, and peptide localization in kidneys subjected to CO2 pneumoperitoneum. METHODS: Experiments were performed in three groups of anesthetized Sprague-Dawley rats in which GFR and UV were measured before, during, and after insufflation. In the first group (n = 8), pneumoperitoneum (10 mmHg) was established for 30 min. The second group (n = 4) underwent a sham operation without pneumoperitoneum. In the final group (n = 4), kidneys were obtained from normal control animals without any prior surgical instrumentation. PreproET-1 (ppET-1) mRNA levels were measured by reverse transcription-polymerase chain reaction (RT-PCR). The ET-1 peptide was localized within kidneys by immunohistochemistry (IHC). RESULTS: Pneumoperitoneum caused a significant (p < 0.05) 87% decrease in GFR and a 79% decrease in UV from baseline, with a return to baseline values after desufflation. RT-PCR showed a significant (p < 0.05) increase in expression of ppET-1 mRNA in the laparoscopic group; it was 3.52 +/- 0.33 densitometric units (DU), as compared to 0.35 +/- 0.06 DU and 0.57 +/- 0.12 DU in the control and sham groups, respectively. IHC showed enhanced expression of the ET-1 peptide in the vascular endothelium and proximal tubular cells of the laparoscopic group compared to the control and sham groups. CONCLUSION: Pneumoperitoneum induces ET-1 gene and peptide upregulation in the kidney. Expression of ET-1 is increased in the renal vasculature and proximal tubular cells. The elevation of ET-1 and its localization may account for some of the renal dysfunction observed during pneumoperitoneum. This suggests that antagonism of ET-1 may be beneficial in patients with renal impairment undergoing prolonged laparoscopic procedures or in protecting allograft function during and after living donor nephrectomy.

Animals↗
PubMed2001

The Skin Picking Scale: scale construction and psychometric analyses.

OBJECTIVE: This paper reports on the development of the Skin Picking Scale (SPS), a six-item paper-and-pencil measure for the assessment of skin picking. METHODS: 28 severe self-injurious and 77 non-self-injurious skin pickers initially completed an eight-item severity scale modeled after the Yale--Brown Obsessive--Compulsive Scale (Y-BOCS). RESULTS: Group comparisons and part--whole correlations for individual scale items resulted in a six-item scale with a total score range of 0--24. A Cronbach's alpha coefficient of.80 indicated moderate internal consistency for the scale. Construct validity was demonstrated by significant correlations between SPS total scale scores and self-reported average duration of skin picking episodes. Significant correlations were also reported between SPS total scale scores and both Beck Depression Inventory (BDI) and Beck Anxiety Inventory (BAI) scores, as well as self-reported intensity of emotions during the picking process. Lastly, sensitivity and specificity analyses suggest that a SPS cut-off score of 7 differentiates severe self-injurious and non-self-injurious skin pickers. CONCLUSION: The SPS is a valid and reliable self-report scale for the assessment of severity in medical and psychiatric patients who endorse skin picking.

Adolescent↗
PubMed2001

Waste form corrosion modeling: comparison with experimental results.

Results of leaching experiments using active and inactively simulated HLW glass in concentrated NaCl solution are described. Measured solution concentrations of glass components, fission products and actinides are compared with computed data. The computed pH value corresponds with the findings from experiments with inactively simulated glass samples. Moreover, the concentrations of silica and strontium can be described adequately by reaction path modelling. The computed U concentration is explained by the precipitation of schoepite or Na2U2O7. The computed Am concentration significantly exceeds the measured data. This may be attributed to sorption processes on corrosion products of the glass, which are relevant also for lanthanide elements under the conditions of the experiments. This hypothesis is tested by solid solution approaches and by computing sorption of Am onto SiO2 precipitates.

Actinoid Series Elements↗
PubMed2001

[Ropivacaine 0.2% versus bupivacaine 0.125% plus sufentanil for continuous peridural analgesia following extended abdominal operations].

OBJECTIVE: An improved opioid-free analgesia concept using thoracic epidural anlgesia with a low concentrated local anaesthetic alone could be of practical interest for hospitals which are unable to guarantee continuous monitoring on the wards. METHODS: We have compared in a prospective, randomized, double-blind study, the analgesic effects and side effects of ropivacaine 0.2% (Group 1) with bupivacaine 0.125% plus 0.5 microgram ml-1 sufentanil (Group 2) via a thoracic epidural catheter during the first 24 hours after major abdominal surgery in 28 gynaecological tumour patients. Assessments were performed 8, 12, 16, 20 and 24 hours after surgery. RESULTS: No differences were seen in duration of surgery, intraoperative opioid and supplemental analgesic requirements. As a main result VAS values for pain during mobilisation were higher in Group 1 when compared with Group 2 (p < 0.01) after 20 and 24 hours of continuous epidural infusion (10 ml h-1) whereas VAS values at rest were comparable (p < 0.1) at all measurepoints. Intensity of motor block and side effects did not differ between groups. CONCLUSION: The present study shows that continuous epidural infusion of 0.2% ropivacaine alone provides comparable analgesia at rest, but less profound pain relief during mobilisation within the first 24 hours after major abdominal surgery than bupivacaine 0.125% with sufentanil.

Abdomen↗
PubMed2001

Subarachnoid sufentanil for early postoperative pain management in orthopedic patients: a placebo-controlled, double-blind study using spinal microcatheters.

BACKGROUND: Continuous spinal anesthesia is frequently used for intraoperative anesthesia but rarely for postoperative pain management. Because even small doses of local anesthetics can be associated with motor deficits, subarachnoid opioid injection may be an alternative. METHODS: Eighty patients randomly received a subarachnoid injection of 10 microg sufentanil, 5 mg bupivacaine, 2.5 microg sufentanil plus 2.5 mg bupivacaine, or saline through 28-gauge spinal microcatheters for early postoperative pain relief after major lower-limb surgery (n = 20 in each group). Hemodynamic and respiratory parameters, pain scores, and motor function were monitored, and sufentanil concentrations in plasma and cerebrospinal fluid were measured. Ten additional patients received up to three repetitive injections of 10 microg sufentanil over 24 h. RESULTS: All drugs provided excellent pain relief within 15 min after injection, lasting 128 +/- 61 min with sufentanil, 146 +/- 74 min with bupivacaine, and 167 +/- 78 min with the mixture. Patients receiving bupivacaine showed the highest cephalad extension of sensory block (median, T6) and the most intense motor block, whereas patients given only sufentanil had no motor deficit. The duration of analgesia was shorter after subsequent sufentanil injection (100-115 min) than after the first injection (198 +/- 70 min). Six of 50 patients with sufentanil experienced a short episode of respiratory depression within 30 min after the first injection. Cerebrospinal fluid concentrations of sufentanil peaked at 5 min after injection (183 +/- 167 ng/ml) but were at the level of detection in the plasma. CONCLUSIONS: Sufentanil injected through microspinal catheters provided profound pain relief without impairing motor function when compared with bupivacaine. However, close monitoring remains mandatory in this setting.

Adult↗
PubMed2001

Renal cell carcinoma in renal graft recipients and donors: incidence and consequence.

INTRODUCTION AND OBJECTIVES: Numerous studies have reported an increasing incidence of small renal cell carcinoma (RCC). De novo RCC in a renal allograft is a rare event and has special implications in renal transplant recipients. The objective of this study was to retrospectively evaluate the incidence of RCC in renal graft recipients and donors and to determine a procedure in cases with newly detected small renal tumors at the time of kidney preparation before transplantation. MATERIAL AND METHODS: We mailed a questionnaire to 38 German transplant clinics and received answers from 27 centers. A total of 10,997 renal graft recipients were included in the period of 1990-1998. RESULTS: In 30 kidneys (0.273%) RCC was detected at the time of preparation before transplantation. There were 23 male and 3 female donors. No bilateral RCC was described. The mean age of the donors with RCC was 50.9 years (range 37-72 years). The tumors had a mean size of 2.2 cm (range 0.4-6 cm). 67% of the patients had a renal tumor smaller than 20 mm. In 26/27 centers the decision to transplant relies on the result of the immediate section for microscopic examination. 16 patients (0.145%) developed RCC 3-12 years after renal transplantation (mean 7.4 years). The mean tumor size was 2.5 cm (range 2-2.8 cm). In 50% a grade 1 and in the other 50% a grade 2 carcinoma was found. CONCLUSIONS: Because of the RCC incidence in donor candidates we recommend an ultrasound screening of the native kidneys before renal explantation and an immediate preparation of the kidney surface especially in donors older than 45 years. In cases with small renal lesions we recommend an immediate section for microscopic examination before transplantation to prevent tumor implantation into an otherwise healthy patient. The frequency of RCCs after renal transplantation necessitates careful clinical and instrumental examinations in organ-transplanted recipients both before and at regular intervals after transplantation, including the patient's kidneys.

Adult↗
PubMed2001

Endocrine alteration in the adrenal gland in kidney transplant patients.

INTRODUCTION: Endocrine alterations associated with chronic renal failure have been reviewed recently. Some of these alterations are of clinical relevance. The aim of this study was to investigate the effect of renal transplantation on the endocrine system of the adrenal gland of the transplant recipients. METHODS: The serum angiotensin-converting enzyme (SACE), plasma renin (PR) and plasma aldosterone (PA) were examined in 30 patients before and after renal allotransplantation. Additionally measured parameters were blood pressure, serum creatinine, potassium, sodium, the duration of dialysis and immunosuppressive medication. RESULTS: Six weeks after renal transplantation, serum creatinine decreased from 820.07 +/- 172.01 to 138.12 +/- 67.54 micromol/l. In the same period, serum potassium decreased from 5.42 +/- 0.89 to 4.17 +/- 0.42 mmol/l. PA and PR decreased from 1,150.84 +/- 976.06 to 233.52 +/- 217.07 micromol/l, and from 121.07 +/- 100.12 to 26.16 +/- 10.86 microU/ml, respectively. SACE decreased from 0.21 +/- 0.21 to 0.13 +/- 0.11 micromol/l. No significant correlation was seen with blood pressure, serum sodium, the duration of dialysis and immunosuppressive drugs. Additionally, 2 patients with acute renal graft dysfunction showed significant increases in PR and PA. After successful treatment both levels declined very quickly to prerejection levels. Patients after binephrectomy show no elevation in PR (5-47 microU/ml) or PA (21-416 micromol/l) neither before nor after renal transplantation. CONCLUSIONS: We conclude that renal transplantation has profound effects on the recipient's renin-angiotensin-aldosterone system. Because of the rapid depression after renal transplantation, it does not appear to be involved in the pathogenesis of post transplantation hypertension but may reflect a role for repair processes after renal allotransplantation.

Adrenal Gland Diseases↗
PubMed2001

Is age at symptom onset associated with severity of memory impairment in adults with obsessive-compulsive disorder?

OBJECTIVE: Age at onset is a potentially important marker for neurobiological features of obsessive-compulsive disorder (OCD). This study examined the relationship between age at symptom onset and memory impairment in adults with OCD. METHOD: The authors used the Rey-Osterrieth Complex Figure Test and the California Verbal Learning Test to compare memory functioning of 37 adult OCD patients with self-reported childhood onset of symptoms (onset at less than 18 years of age) with that of 31 patients with adult-onset symptoms. RESULTS: No differences were found between the two groups on any of the verbal and nonverbal memory measures. CONCLUSIONS: Self-reported age at symptom onset is not associated with memory performance in adult patients with OCD according to tests previously found to be sensitive to frontal-striatal system dysfunction and impairment in OCD. Such dysfunction appears to be a consistent feature of OCD in adults, regardless of age at initial symptom onset.

Adolescent↗
PubMed2001

Prevalence of body dysmorphic disorder in a community sample of women.

OBJECTIVE: In a large population-based study, the authors examined the prevalence and correlates of body dysmorphic disorder, a debilitating and chronic condition characterized by an imagined defect in appearance. METHOD: Rates and diagnostic correlates of body dysmorphic disorder were examined by using data from the Harvard Study of Moods and Cycles. This study used in-person structured clinical interviews to characterize the diagnostic status of a population-based, cross-sectional sample of 318 depressed and 658 nondepressed women between the ages of 36 and 44 who were selected from seven Boston metropolitan area communities. RESULTS: The presence of body dysmorphic disorder was significantly associated with the presence of major depression and anxiety disorders. The authors estimated the overall point prevalence of body dysmorphic disorder as 0.7% in women in this age range in the community. CONCLUSIONS: The authors found that the presence of body dysmorphic disorder was linked to the presence of major depression and anxiety disorders, which is similar to findings in clinical studies. Their estimate of the point prevalence of body dysmorphic disorder is consistent with data from a community-based sample of Italian women and suggests a prevalence similar to that of other serious psychiatric disorders in women (e.g., schizophrenia and drug abuse and dependence). These prevalence data encourage the further development of treatment options for this debilitating condition.

Adult↗
PubMed2001

Discovery of a novel Raf kinase inhibitor.

We discuss the biology of Ras signal transduction and the epidemiology of ras mutations in association with disease as a background for the development of a Raf kinase inhibitor, BAY 43-9006. Knowledge of Ras effector pathways has permitted genetic validation of numerous targets involved in the Ras signaling cascade. A key Ras effector pathway involves the kinase cascade RAF/MEK/ERK (MEK: MAP/ERK kinase; ERK: extracellular signal related kinase). Indeed, we present studies of cell lines stably expressing mutant MEK constructs, which point to Raf kinase as a target for therapeutics with selective anti-tumor activity. Finally, a small molecule drug discovery program based on inhibition of Raf kinase activity is outlined and the initial pre-clinical development process of the Raf kinase inhibitor BAY 43-9006 is discussed.

Animals↗
PubMed2000

The cytoplasmic C-terminal fragment of polycystin-1 regulates a Ca2+-permeable cation channel.

The cytoplasmic C-terminal portion of the polycystin-1 polypeptide (PKD1(1-226)) regulates several important cell signaling pathways, and its deletion suffices to cause autosomal dominant polycystic kidney disease. However, a functional link between PKD1 and the ion transport processes required to drive renal cyst enlargement has remained elusive. We report here that expression at the Xenopus oocyte surface of a transmembrane fusion protein encoding the C-terminal portion of the PKD1 cytoplasmic tail, PKD1(115-226), but not the N-terminal portion, induced a large, Ca(2+)-permeable cation current, which shifted oocyte reversal potential (E(rev)) by +33 mV. Whole cell currents were sensitive to inhibition by La(3+), Gd(3+), and Zn(2+), and partially inhibited by SKF96365 and amiloride. Currents were not activated by bath hypertonicity, but were inhibited by acid pH. Outside-out patches pulled from PKD1(115-226)-expressing oocytes exhibited a 5.1-fold increased NP(o) of endogenous 20-picosiemens cation channels of linear conductance. PKD1(115-226)-injected oocytes also exhibited elevated NP(o) of unitary calcium currents in outside-out and cell-attached patches, and elevated calcium permeability documented by fluorescence ratio and (45)Ca(2+) flux experiments. Both Ca(2+) conductance and influx were inhibited by La(3+). Mutation of candidate phosphorylation sites within PKD1(115-226) abolished the cation current. We conclude that the C-terminal cytoplasmic tail of PKD1 up-regulates inward current that includes a major contribution from Ca(2+)-permeable nonspecific cation channels. Dysregulation of these or similar channels in autosomal dominant polycystic kidney disease may contribute to cyst formation or expansion.

Amino Acid Sequence↗