Dent disease: A window into calcium and phosphate transport

This review examines calcium and phosphate transport in the kidney through the lens of the rare X-linked genetic disorder Dent disease. Dent disease type 1 (DD1) is caused by mutations in the CLCN5 gene encoding ClC-5, a Cl- /H+ antiporter localized to early endosomes of the proximal tubule (PT). Phenotypic features commonly include low molecular weight proteinuria (LMWP), hypercalciuria, focal global sclerosis and chronic kidney disease; calcium nephrolithiasis, nephrocalcinosis and hypophosphatemic rickets are less commonly observed. Although it is not surprising that abnormal endosomal function and recycling in the PT could result in LMWP, it is less clear how ClC-5 dysfunction disturbs calcium and phosphate metabolism. It is known that the majority of calcium and phosphate transport occurs in PT cells, and PT endocytosis is essential for calcium and phosphorus reabsorption in this nephron segment. Evidence from ClC-5 KO models suggests that ClC-5 mediates parathormone endocytosis from tubular fluid. In addition, ClC-5 dysfunction alters expression of the sodium/proton exchanger NHE3 on the PT apical surface thus altering transcellular sodium movement and hence paracellular calcium reabsorption. A potential role for NHE3 dysfunction in the DD1 phenotype has never been investigated, either in DD models or in patients with DD1, even though patients with DD1 exhibit renal sodium and potassium wasting, especially when exposed to even a low dose of thiazide diuretic. Thus, insights from the rare disease DD1 may inform possible underlying mechanisms for the phenotype of hypercalciuria and idiopathic calcium stones

Enhanced Ca(2+) signaling, mild primary aldosteronism, and hypertension in a familial hyperaldosteronism mouse model (Cacna1h(M1560V/+))

Gain-of-function mutations in the CACNA1H gene (encoding the T-type calcium channel Ca(V)3.2) cause autosomal-dominant familial hyperaldosteronism type IV (FH-IV) and early-onset hypertension in humans. We used CRISPR/Cas9 to generate Cacna1h(M1560V/+) knockin mice as a model of the most common FH-IV mutation, along with corresponding knockout mice (Cacna1h(-/-)). Adrenal morphology of both Cacna1h(M1560V/+) and Cacna1h(-/-) mice was normal. Cacna1h(M1560V/+) mice had elevated aldosterone:renin ratios (a screening parameter for primary aldosteronism). Their adrenal Cyp11b2 (aldosterone synthase) expression was increased and remained elevated on a high-salt diet (relative autonomy, characteristic of primary aldosteronism), but plasma aldosterone was only elevated in male animals. The systolic blood pressure of Cacna1h(M1560V/+) mice was 8 mmHg higher than in wild-type littermates and remained elevated on a high-salt diet. Cacna1h(-/-) mice had elevated renal Ren1 (renin-1) expression but normal adrenal Cyp11b2 levels, suggesting that in the absence of Ca(V)3.2, stimulation of the renin-angiotensin system activates alternative calcium entry pathways to maintain normal aldosterone production. On a cellular level, Cacna1h(M1560V/+) adrenal slices showed increased baseline and peak intracellular calcium concentrations in the zona glomerulosa compared to controls, but the frequency of calcium spikes did not rise. We conclude that FH-IV, on a molecular level, is caused by elevated intracellular Ca(2+) concentrations as a signal for aldosterone production in adrenal glomerulosa cells. We demonstrate that a germline Cacna1h gain-of-function mutation is sufficient to cause mild primary aldosteronism, whereas loss of Ca(V)3.2 channel function can be compensated for in a chronic setting

Tonotopically Arranged Traveling Waves in the Miniature Hearing Organ of Bushcrickets

Place based frequency discrimination (tonotopy) is a fundamental property of the coiled mammalian cochlea. Sound vibrations mechanically conducted to the hearing organ manifest themselves into slow moving waves that travel along the length of the organ, also referred to as traveling waves. These traveling waves form the basis of the tonotopic frequency representation in the inner ear of mammals. However, so far, due to the secure housing of the inner ear, these waves only could be measured partially over small accessible regions of the inner ear in a living animal. Here, we demonstrate the existence of tonotopically ordered traveling waves covering most of the length of a miniature hearing organ in the leg of bushcrickets in vivo using laser Doppler vibrometery. The organ is only 1 mm long and its geometry allowed us to investigate almost the entire length with a wide range of stimuli (6 to 60 kHz). The tonotopic location of the traveling wave peak was exponentially related to stimulus frequency. The traveling wave propagated along the hearing organ from the distal (high frequency) to the proximal (low frequency) part of the leg, which is opposite to the propagation direction of incoming sound waves. In addition, we observed a non-linear compression of the velocity response to varying sound pressure levels. The waves are based on the delicate micromechanics of cellular structures different to those of mammals. Hence place based frequency discrimination by traveling waves is a physical phenomenon that presumably evolved in mammals and bushcrickets independently

Lasp-1 Regulates Podosome Function

Eukaryotic cells form a variety of adhesive structures to connect with their environment and to regulate cell motility. In contrast to classical focal adhesions, podosomes, highly dynamic structures of different cell types, are actively engaged in matrix remodelling and degradation. Podosomes are composed of an actin-rich core region surrounded by a ring-like structure containing signalling molecules, motor proteins as well as cytoskeleton-associated proteins

Mate choice for genetic quality when environments vary: suggestions for empirical progress

Mate choice for good-genes remains one of the most controversial evolutionary processes ever proposed. This is partly because strong directional choice should theoretically deplete the genetic variation that explains the evolution of this type of female mating preferences (the so-called lek paradox). Moreover, good-genes benefits are generally assumed to be too small to outweigh opposing direct selection on females. Here, we review recent progress in the study of mate choice for genetic quality, focussing particularly on the potential for genotype by environment interactions (GEIs) to rescue additive genetic variation for quality, and thereby resolve the lek paradox. We raise five questions that we think will stimulate empirical progress in this field, and suggest directions for research in each area: 1) How is condition-dependence affected by environmental variation? 2) How important are GEIs for maintaining additive genetic variance in condition? 3) How much do GEIs reduce the signalling value of male condition? 4) How does GEI affect the multivariate version of the lek paradox? 5) Have mating biases for high-condition males evolved because of indirect benefits

T- and L-type calcium channels maintain calcium oscillations in the murine zona glomerulosa

BACKGROUND: The zona glomerulosa of the adrenal gland is responsible for the synthesis and release of the mineralocorticoid aldosterone. This steroid hormone regulates salt reabsorption in the kidney and blood pressure. The most important stimuli of aldosterone synthesis are the serum concentrations of angiotensin II and potassium. In response to these stimuli, voltage and intracellular calcium levels in the zona glomerulosa oscillate, providing the signal for aldosterone synthesis. It was proposed that the voltage-gated T-type calcium channel Ca(V)3.2 is necessary for the generation of these oscillations. However, Cacna1h knock-out mice have normal plasma aldosterone levels, suggesting additional calcium entry pathways. METHODS: We used a combination of calcium imaging, patch clamp, and RNA sequencing to investigate calcium influx pathways in the murine zona glomerulosa. RESULTS: Cacna1h(-/-) glomerulosa cells still showed calcium oscillations with similar concentrations as wild-type mice. No calcium channels or transporters were upregulated to compensate for the loss of Ca(V)3.2. The calcium oscillations observed were instead dependent on L-type voltage-gated calcium channels. Furthermore, we found that L-type channels can also partially compensate for an acute inhibition of Ca(V)3.2 in wild-type mice. Only inhibition of both T- and L-type calcium channels abolished the increase of intracellular calcium caused by angiotensin II in wild-type. CONCLUSIONS: Our study demonstrates that T-type calcium channels are not strictly required to maintain glomerulosa calcium oscillations and aldosterone production. Pharmacological inhibition of T-type channels alone will likely not significantly impact aldosterone production in the long term