Darier9s disease (DD) is a high penetrance, autosomal dominant mutation in the ATP2A2 gene, which encodes the SERCA2 Ca 2+ pump. Here we have used a mouse model of DD, a SERCA2 +/− mouse, to define the adaptation of Ca 2+ signaling and Ca 2+ ‐dependent exocytosis to a deletion of one copy of the SERCA2 gene. The [Ca 2+ ] i transient evoked by maximal agonist stimulation was shorter in cells from SERCA2 +/− mice, due to an up‐regulation of specific plasma membrane Ca 2+ pump isoforms. The change in cellular Ca 2+ handling caused ∼50% reduction in [Ca 2+ ] i oscillation frequency. Nonetheless, agonist‐stimulated exocytosis was identical in cells from wild‐type and SERCA2 +/− mice. This was due to adaptation in the levels of the Ca 2+ sensors for exocytosis synaptotagmins I and III in cells from SERCA2 +/− mice. Accordingly, exocytosis was ∼10‐fold more sensitive to Ca 2+ in cells from SERCA2 +/− mice. These findings reveal a remarkable plasticity and adaptability of Ca 2+ signaling and Ca 2+ ‐dependent cellular functions in vivo , and can explain the normal function of most physiological systems in DD patients.

/pdf/plasticity-and-adaptation-of-ca2-signaling-and-ca2-dependent-h7mxzltx57.pdf

Plasticity and adaptation of Ca2+ signaling and Ca2+-dependent exocytosis in SERCA2+/− mice

Neonatal pituitary cells express MT1 and MT2 subtype of melatonin receptors that are coupled to pertussis toxin-sensitive G proteins. Their activation by melatonin leads to a decrease in cAMP production and activity of protein kinase A, and attenuation of gonadotropin-releasing hormone (GnRH)-induced gonadotropin secretion. Single cell calcium and electrophysiological recordings have revealed that a reduction in gonadotropin release results from melatonin-induced inhibition of GnRH-stimulated calcium signaling. Melatonin inhibits both calcium influx through voltage-dependent calcium channels and calcium mobilization from intracellular stores. Inhibition of calcium influx, probably in a cAMP/protein kinase C-dependent manner, and the accompanying calcium-induced calcium release from ryanodine-sensitive intracellular pools by melatonin results in a delay of GnRH-induced calcium signaling. Melatonin-induced attenuation of GnRH-induced and inositol (1,4,5)-trisphosphate-mediated calcium release from intracellular pools attenuates the amplitude of calcium signal. The potent inhibition of GnRH-induced calcium signaling and gonadotropin secretion by melatonin provides an effective mechanism to protect premature initiation of pubertal changes that are dependent on plasma gonadotropin levels. During the development, such tonic inhibitory effects of melatonin on GnRH action gradually decline due to a decrease in expression of functional melatonin receptors. In adult animals, melatonin does not have obvious direct effects on pituitary functions, whereas the connections between melatonin release and hypothalamic functions, including GnRH release, are preserved, and are critically important in synchronizing the external photoperiods and reproductive functions through still not well characterized mechanisms.

Melatonin action in neonatal gonadotrophs.

Publisher Summary The pituitary gland is a versatile hormonal interface between the nervous system and the rest of the body, a warehouse of peptides waiting for nervous requisitions In mammals, the anterior pituitary can secrete at least six major peptide hormones from at least five cell types Each cell is under the control of specific releasing hormones and neurotransmitters secreted into the pituitary portal circulation by hypothalamic neurons This chapter describes a study of G protein-mediated modulation of ion channels, which involved working with muscarinic activation of a K+ channel in cardiac trial cells and GnRH and muscarinic inhibition of a K+ channel in frog sympathetic ganglia, where GnRH was a neurotransmitter The work with GnRH has explained the activities of gondaotrope, where a chain of events is triggered by GnRH The primary secretory response to GnRH is unambiguously attributable to a steady rise of IP3that leads to an oscillatory release of Ca2+ from intracellular stores Each elevation brings [Ca2+]i well above the 300 nM level that suffices to initiate exocytosis of numerous secretory granules The secretory stimulus for gonadotropes does not initiate a major entry of extracellular Ca2+ as a primary signal for exocytosis The electrophysiological responses of stimulated gonadotropes include a hyperpolarization during periods of [Ca2+]i rise instead of a depolarization

Signaling mechanisms during the response of pituitary gonadotropes to GnRH.

Pituitary gonadotrophs are a small fraction of the anterior pituitary population, yet they synthesize gonadotropins: luteinizing (LH) and follicle stimulating (FSH), essential for gametogenesis and steroidogenesis. LH is secreted via a regulated pathway while FSH release is mostly constitutive and controlled by synthesis. Although gonadotrophs fire action potentials spontaneously, the intracellular Ca2+ rises produced do not influence secretion, which is mainly driven by Gonadotropin Releasing Hormone (GnRH), a decapeptide synthesized in the hypothalamus and released in a pulsatile manner into the hypophyseal portal circulation. GnRH binding to G protein coupled receptors triggers Ca2+ mobilization from InsP3-sensitive intracellular pools, generating the global Ca2+ elevations necessary for secretion. Ca2+ signaling responses to increasing [GnRH] vary in stereotyped fashion from subthreshold to baseline spiking (oscillatory), to biphasic (spike-oscillatory or spike-plateau). This progression varies somewhat in gonadotrophs from different species and biological preparations. Both baseline spiking and biphasic GnRH-induced Ca2+ signals control LH/FSH synthesis and exocytosis. Estradiol and testosterone regulate gonadotropin secretion through feedback mechanisms, while FSH synthesis and release are influenced by activin, inhibin and follistatin. Adaptation to physiological events like the estrous cycle, involves changes in GnRH sensitivity and LH/FSH synthesis: in proestrus, estradiol feedback regulation abruptly changes from negative to positive, causing the pre-ovulatory LH surge. Similarly, when testosterone levels drop after orquiectomy the lack of negative feedback on pituitary and hypothalamus boosts both GnRH and LH secretion, gonadotrophs GnRH sensitivity increases and Ca2+ signaling patterns change. In addition, gonadotrophs proliferate and grow. These plastic changes denote a more vigorous functional adaptation in response to an extraordinary functional deman

/pdf/gnrh-induced-ca-2-signaling-patterns-and-gonadotropin-2isnr6shgm.pdf

GnRH-Induced Ca(2+) Signaling Patterns and Gonadotropin Secretion in Pituitary Gonadotrophs. Functional Adaptations to Both Ordinary and Extraordinary Physiological Demands.

Mammalian pituitaries exhibit a high degree of intercellular coordination; this enables them to mount large-scale coordinated responses to various physiological stimuli. This type of communication has not been adequately demonstrated in teleost pituitaries, which exhibit direct hypothalamic innervation and expression of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) in distinct cell types. We found that in two fish species, namely tilapia and zebrafish, LH cells exhibit close cell–cell contacts and form a continuous network throughout the gland. FSH cells were more loosely distributed but maintained some degree of cell–cell contact by virtue of cytoplasmic processes. These anatomical differences also manifest themselves at the functional level as evidenced by the effect of gap-junction uncouplers on gonadotropin release. These substances abolished the LH response to gonadotropin-releasing hormone stimulation but did not affect the FSH response to the same stimuli. Dye transfer between neighboring LH cells provides further evidence for functional coupling. The two gonadotropins were also found to be differently packaged within their corresponding cell types. Our findings highlight the evolutionary origin of pituitary cell networks and demonstrate how the different levels of cell–cell coordination within the LH and FSH cell populations are reflected in their distinct secretion patterns.

/pdf/anatomical-and-functional-gonadotrope-networks-in-the-4azbbjofjv.pdf

Anatomical and functional gonadotrope networks in the teleost pituitary.

Our laboratory has been interested in the intracellular signaling mechanisms leading to exocytosis in anterior pituitary cells. The anterior pituitary contains five secretory cell types, each under specific control of releasing hormones and neurotransmitters released by hypothalamic neurons. Surprisingly, the intracellular signals used to turn on different anterior pituitary cells are not all the same. Indeed, the releasing-hormone receptors of the different cell types couple to different G proteins and initiate different second-messenger cascades. For example, gonadotropin-releasing hormone (GnRH) receptors couple to a pertussis toxin-insensitive G protein to activate phospholipase C in gonadotropes, and growth-hormone-releasing hormone (GHRH) receptors couple to G, to activate adenylyl cyclase in somatotropes. How do such different stimuli lead to the common end result, namely, exocytosis of hormones? This report describes a picture of GnRH-mediated signaling in gonadotropes (FIGURE 1) derived from our work and that of others. The approaches we have used combine patch-clamp methods' and fluorescent Ca2+ indicators,2 as we have described b e f ~ r e . ~ ~ In brief, anterior pituitaries of (56)-week-old male rats are dissociated to yield individual cells and are plated for culture. Gonadotropes are positively identified by the reverse-hemolytic-plaque assay and are studied by whole-cell clamp methods to record their ionic currents and membrane capacitance. The intracellular free Caz+ is measured in the single cell by microphotometry with the dye indo-1 loaded into the cell via the recording pipette.

Calcium oscillations and exocytosis in pituitary gonadotropes.

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Calcium oscillations and exocytosis in pituitary gonadotropes.