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Biomedical subjects

B C Schroeder

Publications and source records attributed to B C Schroeder.

8 recordsLinked to original sources
PubMed2000

KCNQ5, a novel potassium channel broadly expressed in brain, mediates M-type currents.

KCNQ2 and KCNQ3, both of which are mutated in a type of human neonatal epilepsy, form heteromeric potassium channels that are expressed in broad regions of the brain. The associated current may be identical to the M-current, an important regulator of neuronal excitability. We now show that the RNA encoding the novel KCNQ5 channel is also expressed in brain and in sympathetic ganglia where it overlaps largely with KCNQ2 and KCNQ3. In addition, it is expressed in skeletal muscle. KCNQ5 yields currents that activate slowly with depolarization and can form heteromeric channels with KCNQ3. Currents expressed from KCNQ5 have voltage dependences and inhibitor sensitivities in common with M-currents. They are also inhibited by M1 muscarinic receptor activation. A KCNQ5 splice variant found in skeletal muscle displays altered gating kinetics. This indicates a molecular diversity of channels yielding M-type currents and suggests a role for KCNQ5 in the regulation of neuronal excitability.

Alternative Splicing↗
PubMed2000

A constitutively open potassium channel formed by KCNQ1 and KCNE3.

Mutations in all four known KCNQ potassium channel alpha-subunit genes lead to human diseases. KCNQ1 (KvLQT1) interacts with the beta-subunit KCNE1 (IsK, minK) to form the slow, depolarization-activated potassium current I(Ks) that is affected in some forms of cardiac arrhythmia. Here we show that the novel beta-subunit KCNE3 markedly changes KCNQ1 properties to yield currents that are nearly instantaneous and depend linearly on voltage. It also suppresses the currents of KCNQ4 and HERG potassium channels. In the intestine, KCNQ1 and KCNE3 messenger RNAs colocalized in crypt cells. This localization and the pharmacology, voltage-dependence and stimulation by cyclic AMP of KCNQ1/KCNE3 currents indicate that these proteins may assemble to form the potassium channel that is important for cyclic AMP-stimulated intestinal chloride secretion and that is involved in secretory diarrhoea and cystic fibrosis.

Amino Acid Sequence↗
PubMed1999

KCNQ4, a novel potassium channel expressed in sensory outer hair cells, is mutated in dominant deafness.

Potassium channels regulate electrical signaling and the ionic composition of biological fluids. Mutations in the three known genes of the KCNQ branch of the K+ channel gene family underlie inherited cardiac arrhythmias (in some cases associated with deafness) and neonatal epilepsy. We have now cloned KCNQ4, a novel member of this branch. It maps to the DFNA2 locus for a form of nonsyndromic dominant deafness. In the cochlea, it is expressed in sensory outer hair cells. A mutation in this gene in a DFNA2 pedigree changes a residue in the KCNQ4 pore region. It abolishes the potassium currents of wild-type KCNQ4 on which it exerts a strong dominant-negative effect. Whereas mutations in KCNQ1 cause deafness by affecting endolymph secretion, the mechanism leading to KCNQ4-related hearing loss is intrinsic to outer hair cells.

Amino Acid Sequence↗
PubMed1998

Moderate loss of function of cyclic-AMP-modulated KCNQ2/KCNQ3 K+ channels causes epilepsy.

Epilepsy affects more than 0.5% of the world's population and has a large genetic component. It is due to an electrical hyperexcitability in the central nervous system. Potassium channels are important regulators of electrical signalling, and benign familial neonatal convulsions (BFNC), an autosomal dominant epilepsy of infancy, is caused by mutations in the KCNQ2 or the KCNQ3 potassium channel genes. Here we show that KCNQ2 and KCNQ3 are distributed broadly in brain with expression patterns that largely overlap. Expression in Xenopus oocytes indicates the formation of heteromeric KCNQ2/KCNQ3 potassium channels with currents that are at least tenfold larger than those of the respective homomeric channels. KCNQ2/KCNQ3 currents can be increased by intracellular cyclic AMP, an effect that depends on an intact phosphorylation site in the KCNQ2 amino terminus. KCNQ2 and KCNQ3 mutations identified in BFNC pedigrees compromised the function of the respective subunits, but exerted no dominant-negative effect on KCNQ2/KCNQ3 heteromeric channels. We predict that a 25% loss of heteromeric KCNQ2/KCNQ3-channel function is sufficient to cause the electrical hyperexcitability in BFNC. Drugs raising intracellular cAMP may prove beneficial in this form of epilepsy.

Amino Acid Sequence↗
PubMed1998

A potassium channel mutation in neonatal human epilepsy.

Benign familial neonatal convulsions (BFNC) is an autosomal dominant epilepsy of infancy, with loci mapped to human chromosomes 20q13.3 and 8q24. By positional cloning, a potassium channel gene (KCNQ2) located on 20q13.3 was isolated and found to be expressed in brain. Expression of KCNQ2 in frog (Xenopus laevis) oocytes led to potassium-selective currents that activated slowly with depolarization. In a large pedigree with BFNC, a five-base pair insertion would delete more than 300 amino acids from the KCNQ2 carboxyl terminus. Expression of the mutant channel did not yield measurable currents. Thus, impairment of potassium-dependent repolarization is likely to cause this age-specific epileptic syndrome.

Action Potentials↗
PubMed1997

Pathophysiological mechanisms of dominant and recessive KVLQT1 K+ channel mutations found in inherited cardiac arrhythmias.

The inherited long QT syndrome (LQTS), characterized by a prolonged QT interval in the electrocardiogram and cardiac arrhythmia, is caused by mutations in at least four different genes, three of which have been identified and encode cardiac ion channels. The most common form of LQTS is due to mutations in the potassium channel gene KVLQT1, but their effects on associated currents are still unknown. Different mutations in KVLQT1 cause the dominant Romano-Ward (RW) syndrome and the recessive Jervell and Lange-Nielsen (JLN) syndrome, which, in addition to cardiac abnormalities, includes congenital deafness. Co-expression of KvLQT1 with the IsK protein elicits slowly activating potassium currents resembling the cardiac Iks current. We now show that IsK not only changes the kinetics of KvLQT1 currents, but also its ion selectivity. Several mutations found in RW, including a novel mutation (D222N) in the putative channel pore, abolish channel activity and reduce the activity of wild-type KvLQT1 by a dominant-negative mechanism. By contrast, a JLN mutation truncating the carboxyterminus of the KvLQT1 channel protein abolishes channel function without having a dominant-negative effect. This fully explains the different patterns of inheritance. Further, we identified a novel splice variant of the KVLQT1 gene, but could not achieve functional expression of this nor of a previously described heart-specific isoform.

Amino Acid Sequence↗
PubMed1995

Epidural analgesia and uterine function.

OBJECTIVE: To determine whether continuous epidural analgesia with bupivacaine and fentanyl affects the rate of cervical dilation and myometrial contractility. METHODS: In a 5-week period, 62 consecutive women who received standardized epidural analgesia were matched with the next two groups of 124 consecutive women of the same parity who did not receive epidural analgesia. The outcome variables were uterine activity, rate of cervical dilation, oxytocin therapy, and operative deliveries. RESULTS: Continuous epidural analgesia with bupivacaine and fentanyl did not result in a change in myometrial contractility in the first hour after the initiation of analgesia. However, despite more oxytocin therapy, the rate of cervical dilation was significantly lower in the epidural group than in the nonepidural group (1.9 versus 5.6 cm/hour, P < .001). Operative deliveries were more common in patients with epidural analgesia than in those without it (12 of 62 versus two of 124, P < .001). CONCLUSION: After epidural analgesia, myometrial contractility is maintained with oxytocin, but the ability of the uterus to dilate the cervix is reduced significantly.

Analgesia, Epidural↗