The atypical 'hippocampal' glutamate receptor coupled to phospholipase D that controls stretch-sensitivity in primary mechanosensory nerve endings is homomeric purely metabotropic GluK2.

A metabotropic glutamate receptor coupled to phospholipase D (PLD-mGluR) was discovered in the hippocampus over three decades ago. Its pharmacology and direct linkage to PLD activation are well established and indicate it is a highly atypical glutamate receptor. A receptor with the same pharmacology is present in spindle primary sensory terminals where its blockade can totally abolish, and its activation can double, the normal stretch-evoked firing.

Stanniocalcin-2 inhibits skeletal muscle growth and is upregulated in functional overload-induced hypertrophy.

Aims: Stanniocalcin-2 (STC2) has recently been implicated in human muscle mass variability by genetic analysis. Biochemically, STC2 inhibits the proteolytic activity of the metalloproteinase PAPP-A, which promotes muscle growth by upregulating the insulin-like growth factor (IGF) axis. The aim was to examine if STC2 affects skeletal muscle mass and to assess how the IGF axis mediates muscle hypertrophy induced by functional overload.

Development of abnormalities at the neuromuscular junction in the SOD1-G93A mouse model of ALS: dysfunction then disruption of postsynaptic structure precede overt motor symptoms.

Introduction: The ultimate deficit in amyotrophic lateral sclerosis (ALS) is neuromuscular junction (NMJ) loss, producing permanent paralysis, ultimately in respiratory muscles. However, understanding the functional and structural deficits at NMJs prior to this loss is crucial for therapeutic strategy design. Should early interventions focus on reversing denervation, or supporting largely intact NMJs that are functionally impaired? We therefore determined when functional and structural deficits appeared in diaphragmatic NMJs relative to the onset of hindlimb tremor (the first overt motor symptoms) in the SOD1-G93A mouse model of ALS.

Biophysical model of muscle spindle encoding.

Muscle spindles encode mechanosensory information by mechanisms that remain only partially understood. Their complexity is expressed in mounting evidence of various molecular mechanisms that play essential roles in muscle mechanics, mechanotransduction and intrinsic modulation of muscle spindle firing behaviour. Biophysical modelling provides a tractable approach to achieve more comprehensive mechanistic understanding of such complex systems that would be difficult/impossible by more traditional, reductionist means.

The Plant Derived 3-3'-Diindolylmethane (DIM) Behaves as CB Receptor Agonist in Prostate Cancer Cellular Models.

3-3'-Diindolylmethane (DIM) is a biologically active dimer derived from the endogenous conversion of indole-3-carbinol (I3C), a naturally occurring glucosinolate found in many cruciferous vegetables (i.e., ).

New functions for the proprioceptive system in skeletal biology.

Muscle spindles and Golgi tendon organs (GTOs) are two types of sensory receptors that respond to changes in length or tension of skeletal muscles. These mechanosensors have long been known to participate in both proprioception and stretch reflex. Here, we present recent findings implicating these organs in maintenance of spine alignment as well as in realignment of fractured bones.

Importance of Full-Collapse Vesicle Exocytosis for Synaptic Fatigue-Resistance at Rat Fast and Slow Muscle Neuromuscular Junctions.

Neurotransmitter release during trains of activity usually involves two vesicle pools (readily releasable pool, or RRP, and reserve pool, or RP) and two exocytosis mechanisms ("full-collapse" and "kiss-and-run"). However, synaptic terminals are adapted to differing patterns of use and the relationship of these factors to enabling terminals to adapt to differing transmitter release demands is not clear. We have therefore tested their contribution to a terminal's ability to maintain release, or synaptic fatiguability in motor terminals innervating fast-twitch (fatiguable), and postural slow-twitch (fatigue-resistant) muscles.

Combined Recording of Mechanically Stimulated Afferent Output and Nerve Terminal Labelling in Mouse Hair Follicle Lanceolate Endings.

A novel dissection and recording technique is described for monitoring afferent firing evoked by mechanical displacement of hairs in the mouse pinna. The technique is very cost-effective and easily undertaken with materials commonly found in most electrophysiology laboratories, or easily purchased. The dissection is simple and fast, with the mechanical displacement provided by a generic electroceramic wafer controlled by proprietary software.

Evidence for the involvement of ASIC3 in sensory mechanotransduction in proprioceptors.

Acid-sensing ion channel 3 (ASIC3) is involved in acid nociception, but its possible role in neurosensory mechanotransduction is disputed. We report here the generation of Asic3-knockout/eGFPf-knockin mice and subsequent characterization of heterogeneous expression of ASIC3 in the dorsal root ganglion (DRG). ASIC3 is expressed in parvalbumin (Pv+) proprioceptor axons innervating muscle spindles.

Optical Monitoring of Living Nerve Terminal Labeling in Hair Follicle Lanceolate Endings of the Ex Vivo Mouse Ear Skin.

A novel dissection and recording technique is described for optical monitoring staining and de-staining of lanceolate terminals surrounding hair follicles in the skin of the mouse pinna. The preparation is simple and relatively fast, reliably yielding extensive regions of multiple labeled units of living nerve terminals to study uptake and release of styryl pyridinium dyes extensively used in studies of vesicle recycling. Subdividing the preparations before labeling allows test vs.

Piezo Is Essential for Amiloride-Sensitive Stretch-Activated Mechanotransduction in Larval Drosophila Dorsal Bipolar Dendritic Sensory Neurons.

Stretch-activated afferent neurons, such as those of mammalian muscle spindles, are essential for proprioception and motor co-ordination, but the underlying mechanisms of mechanotransduction are poorly understood. The dorsal bipolar dendritic (dbd) sensory neurons are putative stretch receptors in the Drosophila larval body wall. We have developed an in vivo protocol to obtain receptor potential recordings from intact dbd neurons in response to stretch.

Synaptic-like vesicles and candidate transduction channels in mechanosensory terminals.

This article summarises progress to date over an exciting and very enjoyable first 15 years of collaboration with Bob Banks. Our collaboration began when I contacted him with (to me) an unexpected observation that a dye used to mark recycling synaptic vesicle membrane at efferent terminals also labelled muscle spindle afferent terminals. This observation led to the re-discovery of a system of small clear vesicles present in all vertebrate primary mechanosensory nerve terminals.

Modelling the mechanoreceptor's dynamic behaviour.

All sensory receptors adapt, i.e. they constantly adjust their sensitivity to external stimuli to match the current demands of the natural environment.

The PDZ-domain protein Whirlin facilitates mechanosensory signaling in mammalian proprioceptors.

Mechanoreception is an essential feature of many sensory modalities. Nevertheless, the mechanisms that govern the conversion of a mechanical force to distinct patterns of action potentials remain poorly understood. Proprioceptive mechanoreceptors reside in skeletal muscle and inform the nervous system of the position of body and limbs in space.

Synthesis and biological evaluation of (-)-kainic acid analogues as phospholipase D-coupled metabotropic glutamate receptor ligands.

(-)-Kainic acid potently increases stretch-induced afferent firing in muscle spindles, probably acting through a hitherto uncloned phospholipase D (PLD)-coupled mGlu receptor. Structural modification of (-)-kainic acid was undertaken to explore the C-4 substituent effect on the pharmacology related to muscle spindle firing. Three analogues 1a-c were synthesised by highly stereoselective additions of a CF3, a hydride and an alkynyl group to the Re face of the key pyrrolidin-4-one intermediate 5a followed by further structural modifications.

A study of the expression of small conductance calcium-activated potassium channels (SK1-3) in sensory endings of muscle spindles and lanceolate endings of hair follicles in the rat.

Processes underlying mechanotransduction and its regulation are poorly understood. Inhibitors of Ca2+-activated K+ channels cause a dramatic increase in afferent output from stretched muscle spindles. We used immunocytochemistry to test for the presence and location of small conductance Ca2+-activated K+ channels (SK1-3) in primary endings of muscle spindles and lanceolate endings of hair follicles in the rat.

Mechanotransduction in the muscle spindle.

The focus of this review is on the principal sensory ending of the mammalian muscle spindle, known as the primary ending. The process of mechanosensory transduction in the primary ending is examined under five headings: (i) action potential responses to defined mechanical stimuli-representing the ending's input-output properties; (ii) the receptor potential-including the currents giving rise to it; (iii) sensory-terminal deformation-measurable changes in the shape of the primary-ending terminals correlated with intrafusal sarcomere length, and what may cause them; (iv) putative stretch-sensitive channels-pharmacological and immunocytochemical clues to their identity; and (v) synaptic-like vesicles-the physiology and pharmacology of an intrinsic glutamatergic system in the primary and other mechanosensory endings, with some thoughts on the possible role of the system. Thus, the review highlights spindle stretch-evoked output is the product of multi-ionic receptor currents plus complex and sophisticated regulatory gain controls, both positive and negative in nature, as befits its status as the most complex sensory organ after the special senses.

Analyses of muscle spindles in the soleus of six inbred mouse strains.

Adult muscle size and fibre-type composition are heritable traits that vary substantially between individuals. We used inbred mouse strains in which soleus muscle mass varied by an order of magnitude to explore whether properties of muscle spindles can also be influenced by genetic factors. Skip-serial cross-sections of soleus muscles dissected from 15 male mice of BEH, BEL, C57BL/6J, DUH, LG/J and SM/J strains were analysed for number of muscle spindles and characteristics of intrafusal and extrafusal fibres following ATPase staining.

Glutamatergic modulation of synaptic-like vesicle recycling in mechanosensory lanceolate nerve terminals of mammalian hair follicles.

Our aim in the present study was to determine whether a glutamatergic modulatory system involving synaptic-like vesicles (SLVs) is present in the lanceolate ending of the mouse and rat hair follicle and, if so, to assess its similarity to that of the rat muscle spindle annulospiral ending we have described previously. Both types of endings are formed by the peripheral sensory terminals of primary mechanosensory dorsal root ganglion cells, so the presence of such a system in the lanceolate ending would provide support for our hypothesis that it is a general property of fundamental importance to the regulation of the responsiveness of the broad class of primary mechanosensory endings. We show not only that an SLV-based system is present in lanceolate endings, but also that there are clear parallels between its operation in the two types of mechanosensory endings.

TGF-beta2 alters the characteristics of the neuromuscular junction by regulating presynaptic quantal size.

The amount of neurotransmitter released from a presynaptic terminal is the product of the quantal content (number of vesicles) and the presynaptic quantal size (QSpre, amount of transmitter per vesicle). QSpre varies with synaptic use, but its regulation is poorly understood. The motor nerve terminals at the neuromuscular junction (NMJ) contain TGF-beta receptors.

Investigation of neuromuscular abnormalities in neurotrophin-3-deficient mice.

Neurotrophin-3 (NT-3) is a trophic factor that is essential for the normal development and maintenance of proprioceptive sensory neurons and is widely implicated as an important modulator of synaptic function and development. We have previously found that animals lacking NT-3 have a number of structural abnormalities in peripheral nerves and skeletal muscles. Here we investigated whether haploinsufficiency-induced reduction in NT-3 resulted in impaired neuromuscular performance and synaptic function.

Amiloride-sensitive channels are a major contributor to mechanotransduction in mammalian muscle spindles.

We investigated whether channels of the epithelial sodium/amiloride-sensitive degenerin (ENaC/DEG) family are a major contributor to mechanosensory transduction in primary mechanosensory afferents, using adult rat muscle spindles as a model system. Stretch-evoked afferent discharge was reduced in a dose-dependent manner by amiloride and three analogues - benzamil, 5-(N-ethyl-N-isopropyl) amiloride (EIPA) and hexamethyleneamiloride (HMA), reaching > or = 85% inhibition at 1 mm. Moreover, firing was slightly but significantly increased by ENaC delta subunit agonists (icilin and capsazepine).

Autogenic modulation of mechanoreceptor excitability by glutamate release from synaptic-like vesicles: evidence from the rat muscle spindle primary sensory ending.

Fifty-nanometre diameter, clear, synaptic-like vesicles (SLVs) are found in primary mechanosensory nerve terminals of vertebrate and invertebrate animals. We have investigated their role in mechanosensory function using the muscle spindle primary endings of rat Ia afferents as a model. Uptake and release of the synaptic vesicle marker FM1-43 indicated that SLVs recycle like synaptic vesicles and do so in a Ca(2+)-sensitive manner.