InsP3-induced Ca2+ excitability of the endoplasmic reticulum (original) (raw)

Neuronal endoplasmic reticulum acts as a single functional Ca 2+ store shared by ryanodine and inositol-1,4,5-trisphosphate receptors as revealed by intra-ER [Ca 2+ ] recordings in single rat sensory neurones

Pfl�gers Archiv European Journal of Physiology, 2003

Neuronal endoplasmic reticulum acts as a single functional Ca 2+ store shared by ryanodine and inositol-1,4,5-trisphosphate receptors as revealed by intra-ER [Ca 2+ ] recordings in single rat sensory neurones Abstract We addressed the fundamentally important question of functional continuity of endoplasmic reticulum (ER) Ca 2+ store in nerve cells. In cultured rat dorsal root ganglion neurones we measured dynamic changes in free Ca 2+ concentration within the ER lumen ([Ca 2+ ] L ) in response to activation of inositol-1,4,5-trisphosphate receptors (InsP 3 Rs) and ryanodine receptors (RyRs). We found that both receptors co-exist in these neurones and their activation results in Ca 2+ release from the ER as judged by a decrease in [Ca 2+ ] L . Depletion of Ca 2+ stores following an inhibition of sarco(endoplasmic)reticulum Ca 2+ -ATPase by thapsigargin or cyclopiazonic acid completely eliminated Ca 2+ release via both InsP 3 Rs and RyRs. Similarly, when the store was depleted by continuous activation of InsP 3 Rs, activation of RyRs (by caffeine or 0.5 mM ryanodine) failed to produce Ca 2+ release, and vice versa, when the stores were depleted by activators of RyRs, the InsP 3 -induced Ca 2+ release disappeared. We conclude that in mammalian neurones InsP 3 Rs and RyRs share the common continuous Ca 2+ pool associated with ER.

Signals 2 + )-evoked Ca 3 Promotes Inositol Trisphosphate ( IP Store Filling by Cyclic ADP-ribose 2 + Modulation of Endoplasmic Reticulum Ca Signal Transduction

2010

In addition to its well established function in activating Ca 2؉ release from the endoplasmic reticulum (ER) through ryanodine receptors (RyR), the second messenger cyclic ADP-ribose (cADPR) also accelerates the activity of SERCA pumps, which sequester Ca 2؉ into the ER. Here, we demonstrate a potential physiological role for cADPR in modulating cellular Ca 2؉ signals via changes in ER Ca 2؉ store content, by imaging Ca 2؉ liberation through inositol trisphosphate receptors (IP 3 R) in Xenopus oocytes, which lack RyR. Oocytes were injected with the non-metabolizable analog 3-deaza-cADPR, and cytosolic [Ca 2؉ ] was transiently elevated by applying voltage-clamp pulses to induce Ca 2؉ influx through expressed plasmalemmal nicotinic channels. We observed a subsequent potentiation of global Ca 2؉ signals evoked by strong photorelease of IP 3 , and increased numbers of local Ca 2؉ puffs evoked by weaker photorelease. These effects were not evident with cADPR alone or following cytosolic Ca 2؉ elevation alone, indicating that they did not arise through direct actions of cADPR or Ca 2؉ on the IP 3 R, but likely resulted from enhanced ER store filling. Moreover, the appearance of a new population of puffs with longer latencies, prolonged durations, and attenuated amplitudes suggests that luminal ER Ca 2؉ may modulate IP 3 R function, in addition to simply determining the size of the available store and the electrochemical driving force for release.

Intracellular calcium channels and their modulators

Expert Opinion on Therapeutic Patents, 2003

The ryanodine receptor (RyR) is an essential element in excitation-contraction coupling. Ca 2+ release from the sarcoplasmic reticulum (SR) is required for skeletal and heart muscle contraction. The inositol-1,4,5-triphosphatereceptor (IP 3 R) plays an important function in the signal transduction of many hormones, cytokines, growth factors and antigens, and in fertilisation. Modulators of intracellular calcium channels are used for the treatment of malignant hyperthermia associated with abnormal Ca 2+ transport and may be applied in the treatment of cardiovascular and neurodegenerative disorders.

IP3 receptors and Ca2+ entry

Biochimica et Biophysica Acta (BBA) - Molecular Cell Research, 2018

Inositol 1,4,5-trisphosphate receptors (IP 3 R) are the most widely expressed intracellular Ca 2+ release channels. Their activation by IP 3 and Ca 2+ allows Ca 2+ to pass rapidly from the ER lumen to the cytosol. The resulting increase in cytosolic [Ca 2+ ] may directly regulate cytosolic effectors or fuel Ca 2+ uptake by other organelles, while the decrease in ER luminal [Ca 2+ ] stimulates store-operated Ca 2+ entry (SOCE). We are close to understanding the structural basis of both IP 3 R activation, and the interactions between the ER Ca 2+-sensor, STIM, and the plasma membrane Ca 2+ channel, Orai, that lead to SOCE. IP 3 Rs are the usual means through which extracellular stimuli, through ER Ca 2+ release, stimulate SOCE. Here, we review evidence that the IP 3 Rs most likely to respond to IP 3 are optimally placed to allow regulation of SOCE. We also consider evidence that IP 3 Rs may regulate SOCE downstream of their ability to deplete ER Ca 2+ stores. Finally, we review evidence that IP 3 Rs in the plasma membrane can also directly mediate Ca 2+ entry in some cells.

The endoplasmic reticulum and neuronal calcium signalling

Cell Calcium, 2002

The endoplasmic reticulum (ER) is a multifunctional signalling organelle regulating a wide range of neuronal functional responses. The ER is intimately involved in intracellular Ca 2+ signalling, producing local or global cytosolic calcium fluctuations via Ca 2+ -induced Ca 2+ release (CICR) or inositol-1,4,5-trisphosphate-induced Ca 2+ release (IICR). The CICR and IICR are controlled by two subsets of Ca 2+ release channels residing in the ER membrane, the Ca 2+ -gated Ca 2+ release channels, generally known as ryanodine receptors (RyRs) and InsP 3 -gated Ca 2+ release channels, referred to as InsP 3 -receptors (InsP 3 Rs). Both types of Ca 2+ release channels are expressed abundantly in nerve cells and their activation triggers cytoplasmic Ca 2+ signals important for synaptic transmission and plasticity. The RyRs and InsP 3 Rs show heterogeneous localisation in distinct cellular sub-compartments, conferring thus specificity in local Ca 2+ signals. At the same time, the ER Ca 2+ store emerges as a single interconnected pool fenced by the endomembrane. The continuity of the ER Ca 2+ store could play an important role in various aspects of neuronal signalling. For example, Ca 2+ ions may diffuse within the ER lumen with comparative ease, endowing this organelle with the capacity for "Ca 2+ tunnelling". Thus, continuous intra-ER Ca 2+ highways may be very important for the rapid replenishment of parts of the pool subjected to excessive stimulation (e.g. in small compartments within dendritic spines), the facilitated removal of localised Ca 2+ loads, and finally in conveying Ca 2+ signals from the site of entry towards the cell interior and nucleus.

Interaction between Ca2+ release from inositol trisphosphate sensitive stores and Ca2+ entry through neuronal Ca2+ channels expressed in Xenopus oocyte

Cell Calcium, 1994

Rat cerebeiiar RNA injected into Xenopus oocytes leads to the expression of putative P-type vottagedependent Ca2+ channels (VDCCS). The monitoring of intraceiiuiar Ca2' variations by recording the Ca2' dsip"dent chloride current in voltage clamped oocytes indicates that activation of these Ca + channels by depoiarization gives rise to two distinct components of cytosoiic Ca2+ elevation. if the eariy component (Tr) can be di aMbuted to the Ca2+ entry through VDCCs, the second one4(T2)ls~toa + 3 reiease from insP3 sensitive stores activated following entry. Modlficaflons of cyt* soiic Ca2+ by direct ln)ection of c$+ into oocytes or by increasing the Q?+ influx through VDCCs suggest that the Ca2' release from intraceliuiar InsPs sensitive stores can be modulated in a dffferentiai manner. Nameiy, discrete elevations of cytosoiic Ca2+ switch on the Ca2' release whereas higher Ca2+ concentrations dampen the release.