Calcium dependence of both lobes of calmodulin is involved in binding to a cytoplasmic domain of SK channels.

KCa2.1-3 Ca-activated K-channels (SK) require calmodulin to gate in response to cellular Ca. A model for SK gating proposes that the N-terminal domain (N-lobe) of calmodulin is required for activation, but an immobile C-terminal domain (C-lobe) has constitutive, Ca-independent binding.

Non-Additive Effects of Binding Site Mutations in Calmodulin.

Despite decades of research on ion-sensing proteins, gaps persist in the understanding of ion binding affinity and selectivity even in well-studied proteins such as calmodulin. Site-directed mutagenesis is a powerful and popular tool for addressing outstanding questions about biological ion binding and is employed to selectively deactivate binding sites and insert chromophores at advantageous positions within ion binding structures. However, even apparently nonperturbative mutations can distort the binding dynamics they are employed to measure.

Electrostatic Tuning of a Potassium Channel in Electric Fish.

Molecular variation contributes to the evolution of adaptive phenotypes, though it is often difficult to understand precisely how. The adaptively significant electric organ discharge behavior of weakly electric fish is the direct result of biophysical membrane properties set by ion channels. Here, we describe a voltage-gated potassium-channel gene in African electric fishes that is under positive selection and highly expressed in the electric organ.

Coordination to lanthanide ions distorts binding site conformation in calmodulin.

The Ca-sensing protein calmodulin (CaM) is a popular model of biological ion binding since it is both experimentally tractable and essential to survival in all eukaryotic cells. CaM modulates hundreds of target proteins and is sensitive to complex patterns of Ca exposure, indicating that it functions as a sophisticated dynamic transducer rather than a simple on/off switch. Many details of this transduction function are not well understood.

Conserved properties of individual Ca2+-binding sites in calmodulin.

Calmodulin (CaM) is a Ca(2+)-sensing protein that is highly conserved and ubiquitous in eukaryotes. In humans it is a locus of life-threatening cardiomyopathies. The primary function of CaM is to transduce Ca(2+) concentration into cellular signals by binding to a wide range of target proteins in a Ca(2+)-dependent manner.

Calcium-dependent stoichiometries of the KCa2.2 (SK) intracellular domain/calmodulin complex in solution.

Ca(2+) activates SK Ca(2+)-activated K(+) channels through the protein Ca(2+) sensor, calmodulin (CaM). To understand how SK channels operate, it is necessary to determine how Ca(2+) regulates CaM binding to its target on SK. Tagless, recombinant SK peptide (SKp), was purified for binding studies with CaM at low and high Ca(2+) concentrations.

Alternatively spliced domains interact to regulate BK potassium channel gating.

Most human genes contain multiple alternative splice sites believed to extend the complexity and diversity of the proteome. However, little is known about how interactions among alternative exons regulate protein function. We used the Caenorhabditis elegans slo-1 large-conductance calcium and voltage-activated potassium (BK) channel gene, which contains three alternative splice sites (A, B, and C) and encodes at least 12 splice variants, to investigate the functional consequences of alternative splicing.

EF hands at the N-lobe of calmodulin are required for both SK channel gating and stable SK-calmodulin interaction.

Small conductance calcium-activated potassium (SK) channels respond to intracellular Ca(2+) via constitutively associated calmodulin (CaM). Previous studies have proposed a modular design for the interaction between CaM and SK channels. The C-lobe and the linker of CaM are thought to regulate the constitutive binding, whereas the N-lobe binds Ca(2+) and gates SK channels.

Determinants in CaV1 channels that regulate the Ca2+ sensitivity of bound calmodulin.

Calmodulin binds to IQ motifs in the alpha(1) subunit of Ca(V)1.1 and Ca(V)1.2, but the affinities of calmodulin for the motif and for Ca(2+) are higher when bound to Ca(V)1.

Regulation of voltage-gated Ca2+ channels by calmodulin.

Calmodulin, a highly versatile and ubiquitously expressed Ca2+ sensor, regulates the function of many enzymes and ion channels. Both Ca2+-dependent inactivation and Ca2+-dependent facilitation of the voltage-gated Ca2+ channels Cav1.2 andCav2.

Regulation of voltage-gated Ca2+ channels by calmodulin.

Calmodulin, a highly versatile and ubiquitously expressed Ca2+ sensor, regulates the function of many enzymes and ion channels. Both Ca2+-dependent inactivation and Ca2+-dependent facilitation of the voltage-gated Ca2+ channels Cav1.2 and Cav2.

Structure of calmodulin bound to the hydrophobic IQ domain of the cardiac Ca(v)1.2 calcium channel.

Ca2+-dependent inactivation (CDI) and facilitation (CDF) of the Ca(v)1.2 Ca2+ channel require calmodulin binding to a putative IQ motif in the carboxy-terminal tail of the pore-forming subunit. We present the 1.

Calmodulin interactions with IQ peptides from voltage-dependent calcium channels.

Calmodulin (CaM) functions as a Ca(2+) sensor for inactivation and, in some cases, facilitation of a variety of voltage-dependent Ca(2+) channels. A crucial determinant for CaM binding to these channels is the IQ motif in the COOH-terminal tail of the channel-forming subunit. The binding of CaM to IQ peptides from Lc-, P/Q-, and R-type, but not N-type, voltage-dependent Ca(2+) channels increases the Ca(2+) affinity of both lobes of CaM, producing similar N- and C-lobe Ca(2+) affinities.

Apocalmodulin and Ca2+ calmodulin-binding sites on the CaV1.2 channel.

The cardiac L-type voltage-dependent calcium channel is responsible for initiating excitation-contraction coupling. Three sequences (amino acids 1609-1628, 1627-1652, and 1665-1685, designated A, C, and IQ, respectively) of its alpha(1) subunit contribute to calmodulin (CaM) binding and Ca(2+)-dependent inactivation. Peptides matching the A, C, and IQ sequences all bind Ca(2+)CaM.

Coupling of RYR1 and L-type calcium channels via calmodulin binding domains.

In skeletal muscle the L-type Ca2+ channel directly controls the opening of the sarcoplasmic reticulum Ca2+ release channel (RYR1), and RYR1, in turn, prevents L-type Ca2+ channel inactivation. We demonstrate that the two proteins interact using calmodulin binding regions of both proteins. A recombinant protein representing amino acids 1393-1527 (D1393-1527) of the carboxyl-terminal tail of the skeletal muscle L-type voltage-dependent calcium channel binds Ca2+, Ca2+ calmodulin, and apocalmodulin.

Factors affecting the recognition of reverberant speech by elderly listeners.

Elderly listeners have been shown to experience greater difficulty with speech understanding than young listeners. The greater difficulty with speech understanding in elderly listeners has been attributed, primarily, to their typical high-frequency sensorineural hearing impairment. However, not all of the observed difficulty can be accounted for by hearing thresholds, leaving the likelihood of additional suprathreshold processing deficits.

Reliability and stability of various hearing-aid outcome measures in a group of elderly hearing-aid wearers.

Twenty elderly persons with hearing impairment were fit with binaural in-the-ear hearing aids and followed for a 6-month period post-fit. Several hearing-aid outcome measures were obtained at 0, 7, 15, 30, 60, 90, and 180 days post-fit. Outcome measures included (a) objective measures of benefit obtained with nonsense-syllable materials in quiet (CUNY Nonsense Syllable Test, NST) and sentences in multitalker babble (Hearing in Noise Test, HINT); (b) two subjective measures of benefit, one derived from pre-fit/post-fit comparisons on a general scale of hearing handicap (Hearing Handicap Inventory for the Elderly, HHIE) and the other based on a subjective scale of post-fit hearing-aid benefit (Hearing Aid Performance Inventory, HAPI); (c) a questionnaire on hearing-aid satisfaction; (d) an objective measure of hearing-aid use; and (e) a subjective measure of hearing-aid use.

Factors associated with individual differences in clinical measures of speech recognition among the elderly.

In the present study, the speech-recognition performance of 50 subjects aged 63 to 83 years was measured for a wide range of materials (nonsense syllables, monosyllabic words, sentences) and listening conditions (presentation levels of 70 and 90 dB SPL, both in quiet and in a noise background). In addition to complete audiologic evaluations, measures of auditory processing (the Test of Basic Auditory Capabilities [TBAC], Watson, 1987) and cognitive function (Wechsler Adult Intelligence Scale-Revised [WAIS-R], and the Wechsler Memory Scale-Revised [WMS-R], Wechsler, 1981, 1987) were obtained from all subjects. Principal component analyses were applied to each of the three sets of measures (speech-recognition, auditory, and cognitive) prior to examining associations among the sets using canonical analyses.