Membrane guanylate cyclase, a multimodal transduction machine: history, present, and future directions

A sequel to these authors’ earlier comprehensive reviews which covered the field of mammalian membrane guanylate cyclase (MGC) from its origin to the year 2010, this article contains 13 parts. The first is HISTORICAL and covers MGC from the year 1963-1987, summarizing its colorful developmental stages from its passionate pursuit to its consolidation. The second deals with the establishment of its BIOCHEMICAL IDENTITY. MGC becomes the transducer of a hormonal signal and founder of the peptide hormone receptor family, and creates the notion that hormone signal transduction is its sole physiological function. The third defines its EXPANSION. The discovery of ROS-GC subfamily is made and it links ROS-GC with the physiology of PHOTOTRANSDUCTION. Parts 4 to 7 cover its BIOCHEMISTRY and PHYSIOLOGY. The noteworthy events are that augmented by GCAPs, ROS-GC proves to be a transducer of the free Ca2+ signals generated within neurons; ROS-GC becomes a two-component transduction system and establishes itself as a source of cyclic GMP, the second messenger of phototransduction. Part 8 demonstrates how this knowledge begins to be TRANSLATED into the diagnosis and providing the molecular definition of retinal dystrophies. Part 9 discusses a striking property of ROS-GC where it becomes a [Ca2+]i bimodal switch and transcends its signaling role in other neural transduction processes. In this course, discovery of the first CD-GCAP (Ca2+-dependent guanylate cycles activator), the S100B protein, is made. It extends the role of ROS-GC transduction system beyond the photoreceptor cells to the signaling processes in the synapse region between photoreceptor and cone ON-bipolar cells; in Part 10, discovery of ANOTHER CD-GCAP, NC, is made and its linkage with signaling of the inner plexiform layer neurons is established. Part 11 discusses linkage of the ROS-GC transduction system with other sensory transduction processes: Pineal gland, Olfaction and Gustation. In the next, part 12, a the

Ca2+-sensors and ROS-GC: interlocked sensory transduction elements: a review

From its initial discovery that ROS-GC membrane guanylate cyclase is a mono-modal Ca2+-transduction system linked exclusively with the photo-transduction machinery to the successive finding that it embodies a remarkable bimodal Ca2+ signaling device, its widened transduction role in the general signaling mechanisms of the sensory neuron cells was envisioned. A theoretical concept was proposed where Ca2+-modulates ROS-GC through its generated cyclic GMP via a nearby cyclic nucleotide gated channel and creates a hyper- or depolarized sate in the neuron membrane (Ca2+ Binding Proteins 1:1, 7–11, 2006). The generated electric potential then becomes a mode of transmission of the parent [Ca2+]i signal. Ca2+ and ROS-GC are interlocked messengers in multiple sensory transduction mechanisms. This comprehensive review discusses the developmental stages to the present status of this concept and demonstrates how neuronal Ca2+-sensor (NCS) proteins are the interconnected elements of this elegant ROS-GC transduction system. The focus is on the dynamism of the structural composition of this system, and how it accommodates selectivity and elasticity for the Ca2+ signals to perform multiple tasks linked with the SENSES of vision, smell, and possibly of taste and the pineal gland. An intriguing illustration is provided for the Ca2+ sensor GCAP1 which displays its remarkable ability for its flexibility in function from being a photoreceptor sensor to an odorant receptor sensor. In doing so it reverses its function from an inhibitor of ROS-GC to the stimulator of ONE-GC membrane guanylate cyclase

Neurocalcin δ Modulation of ROS-GC1, a New Model of Ca2+ Signaling†

ROS-GC1 membrane guanylate cyclase is a Ca(2+) bimodal signal transduction switch. It is turned off by a rise in free Ca(2+) from nanomolar to the semicromolar range in the photoreceptor outer segments and the olfactory bulb neurons; by a similar rise in the bipolar and ganglion retinal neurons it is turned on . These opposite operational modes of the switch are specified by its Ca(2+) sensing devices, respectively termed GCAPs and CD-GCAPs. Neurocalcin delta is a CD-GCAP. In the present study, the neurocalcin delta-modulated site, V(837)-L(858), in ROS-GC1 has been mapped. The location and properties of this site are unique. It resides within the core domain of the catalytic module and does not require the alpha-helical dimerization domain structural element (amino acids 767-811) for activating the catalytic module. Contrary to the current beliefs, the catalytic module is intrinsically active; it is directly regulated by the neurocalcin delta-modulated Ca(2+) signal and is dimeric in nature. A fold recognition based model of the catalytic domain of ROS-GC1 was built, and neurocalcin delta docking simulations were carried out to define the three-dimensional features of the interacting domains of the two molecules. These findings define a new transduction model for the Ca(2+) signaling of ROS-GC1

Quantification of edema in edematous severe acute malnutrition children aged 6 months to 5 years

Background: Malnutrition is rampant in India, and edematous severe acute malnutrition (SAM) is associated with high morbidity and mortality. Clinical grading of edema in these children is known, but still, no quantification has been described. Objective: The objective of this study was to quantify the edema in children with edematous SAM (E-SAM). Materials and Methods: This prospective study was conducted over a period of 1 year in 2016 at a malnutrition treatment center of tertiary hospital attached to a medical college. 50 children were selected with E-SAM between 6 months and 5 years of age. The sick children, needing intensive care unit care and having edema other than nutritional cause, were excluded from the study. These children were examined daily for any change in the status of edema by comparing the change in the weight, which was taken using electronic weighing scale. The weight at which child has no edema and no fall in weight for 2 consecutive days was defined as dry weight of the child. All the children were evaluated regarding the onset of loss of edema, days taken for complete disappearance of edema, weight loss per day, mean loss of weight, etc. Results: Of 50 children with E-SAM, 28 were male and 22 were females. Mean age of children was 16.5±11.04 months. The admitted children had +2 edema (26%), followed by +3 edema (17%), while only 7 (14%) children had +1 edema. The mean age of moderate-to-severe edematous children was 13 months. These children started losing edema by day 3 (3.22±0.9) and the mean number of days for complete disappearance of edema was 10.02±2.8 days. The mean percent weight loss was 1% per day and did not vary with different grades of edema (p>0.5). The percentage loss of total weight was maximum for children with +3 edema being 13%, followed by 10% in +2, and 5% in +1 edema which was statistically significant (p=0.004). Conclusions: E-SAM children have grade +1, +2, and +3 edema which are equivalent to 5%, 10%, and >10% over to their actual weight, respectively, and younger children are more susceptible to moderate-to-severe edema

ROS-GC interlocked Ca2+-sensor S100B protein signaling in cone photoreceptors: review

Photoreceptor rod outer segment membrane guanylate cyclase (ROS-GC) is central to visual transduction; it generates cyclic GMP, the second messenger of the photon signal. Photoexcited rhodopsin initiates a biochemical cascade that leads to a drop in the intracellular level of cyclic GMP and closure of cyclic nucleotide gated ion channels. Recovery of the photoresponse requires resynthesis of cyclic GMP, typically by a pair of ROS-GCs, 1 and 2. In rods, ROS-GCs exist as complexes with guanylate cyclase activating proteins (GCAPs), which are Ca2+-sensing elements. There is a light-induced fall in intracellular Ca2+. As Ca2+ dissociates from GCAPs in the 20–200 nM range, ROS-GC activity rises to quicken the photoresponse recovery. GCAPs then progressively turn down ROS-GC activity as Ca2+ and cyclic GMP levels return to baseline. To date, GCAPs mediate the only known mechanism of ROS-GC regulation in the photoreceptors. However, in mammalian cone outer segments, cone synapses and ON bipolar cells, another Ca2+ sensor protein, S100B, complexes with ROS-GC1 and senses the Ca2+ signal with a K1/2 of 400 nM. Unlike GCAPs, S100B stimulates ROS-GC activity when Ca2+ is bound. Thus, the ROS-GC system in cones functions as a Ca2+ bimodal switch; with rising intracellular Ca2+, its activity is first turned down by GCAPs and then turned up by S100B. This presentation provides a historical perspective on the role of S100B in the photoreceptors, offers a pictorial model for the “bimodal” operation of the ROS-GC switch and projects future tasks that are needed to understand its operation. Some accounts of this review have been adopted from the original publications of these authors

Multilimbed membrane guanylate cyclase signaling system, evolutionary ladder

One monumental discovery in the field of cell biology is the establishment of the membrane guanylate cyclase signal transduction system. Decoding its fundamental, molecular, biochemical, and genetic features revolutionized the processes of developing therapies for diseases of endocrinology, cardio-vasculature, and sensory neurons; lastly, it has started to leave its imprints with the atmospheric carbon dioxide. The membrane guanylate cyclase does so via its multi-limbed structure. The inter-netted limbs throughout the central, sympathetic, and parasympathetic systems perform these functions. They generate their common second messenger, cyclic GMP to affect the physiology. This review describes an historical account of their sequential evolutionary development, their structural components and their mechanisms of interaction. The foundational principles were laid down by the discovery of its first limb, the ACTH modulated signaling pathway (the companion monograph). It challenged two general existing dogmas at the time. First, there was the question of the existence of a membrane guanylate cyclase independent from a soluble form that was heme-regulated. Second, the sole known cyclic AMP three-component-transduction system was modulated by GTP-binding proteins, so there was the question of whether a one-component transduction system could exclusively modulate cyclic GMP in response to the polypeptide hormone, ACTH. The present review moves past the first question and narrates the evolution and complexity of the cyclic GMP signaling pathway. Besides ACTH, there are at least five additional limbs. Each embodies a unique modular design to perform a specific physiological function; exemplified by ATP binding and phosphorylation, Ca2+-sensor proteins that either increase or decrease cyclic GMP synthesis, co-expression of antithetical Ca2+ sensors, GCAP1 and S100B, and modulation by atmospheric carbon dioxide and temperature. The complexity provided by these various manners of operation enables membrane guanylate cyclase to conduct diverse functions, exemplified by the control over cardiovasculature, sensory neurons and, endocrine systems

FILARIASIS PRESENTING AS AN EPIDIDYMAL NODULE: AN UNUSUAL PRESENTATION - CASE REPORT

Introduction Lymphatic filariasis is a public health problem in India. Main clinical features of chronic Bancroftian filariasis are hydrocele, elephantiasis and chyluria .We present an unusual case of genital filariasis which presented with microfilaria in epididymal nodule. Case presentation 35 year old man presented with a history of swelling in left epididymis for last 3 months insidious in onset and associated with mild pain. On examination there was a palpable, tender and firm nodule measuring 2 cm x1.5 cms in the left epididymis. FNAC revealed multiple microfilaria of W.bancrofti present in coiled and elongated forms and confirmed by the presence of sheath and absence of nuclei from tip and tail. The rest of the population comprised of neutrophils admixed with eosinophils lying in a partly haemorrhagic background. Conclusion FNAC has proved useful. This is unusual presentation of genital filariasis where microfiliaria have been reported in epididymal nodule

Identification and Validation of Resistance to Fusarium Wilt and Sterility Mosaic Disease in Pigeonpea

Fusarium wilt (FW) and Sterility mosaic disease (SMD) are the two important diseases of pigeonpea (Cajanus cajan) worldwide, and best managed through host plant resistance. The aim of the work was to identify and validate new sources to wilt and SMD in pigeonpea. Preliminary evaluation of 3000 germplasm and breeding lines was carried out at International Crop Research Institute for Semi Arid Tropics (ICRISAT) for FW and SMD resistance in sick plot during 2005/06 crop season to 2007/08. Sixty lines with < 10% FW and SMD incidence were selected from 3000 germplasm and breeding lines and these lines were evaluated repeatedly for three consecutive years during 2008/09, 2009/10 and 2010/11 crop seasons for their stability against both the diseases. Fifty-four lines were found resistant to FW and high level of resistance to SMD was found in all the 60 lines. Combined resistance to FW and SMD was found in 54 lines, of which, one line (ICPL 20108) was found asymptomatic. These resistant lines can be exploited for crossing with commercial cultivars to develop pigeonpea varieties with adequate levels of multiple resistances to enhance pigeonpea production in the Indian subcontinent

A 5 year retrospective study on epidemiological pattern of ocular trauma

Background: One of the delicate structure in the human body is eye and trauma to the eye is essentially a very grave matter. Major cause of preventable monocular blindness and visual impairment in the world is ocular trauma. So any injury to the eye must be deemed to be an ocular emergency and should be handled with utmost care. Despite its public health importance, there is relatively less population based data on the magnitude and risk factors for ocular trauma specially from developing countries. The objective of the study was to find out the epidemiological pattern of ocular trauma.Methods: The present study was 5 year retrospective study of all the patients who reported directly with ocular injury or referred from the casualty to the department of ophthalmology from January 2013 to January 2018. Various parameters like age, sex, mode of injury, type of injury etc. of all patients seen during this period were analyzed.Results: Total of 4192 ocular trauma patients were seen during study period. Maximum number of ocular trauma patients i.e. 1146 were seen in age group of 21-30 years. Males i.e. 3490 outnumbered females in the present study. Road traffic accidents were the most common cause of ocular trauma and accounts for 1760 cases. Most common reported ocular trauma was periorbital oedema/ecchymosis followed by laceration. Surgical intervention was done in 1660 cases whereas 2532 were managed medically.Conclusions: From present study, we may conclude that the maximum number of ocular trauma patients were seen in the age group of 21-30 years with more preponderance in males. Road traffic accidents were the most common cause of ocular trauma. The fact that the lifetime prevalence of ocular trauma is higher than that of eye diseases, which can be decreased by implementing the traffic rules with strict force and imposing heavy fine and license cancellation for drunken driving