P2x7

Yes*

BBGe

No

No

No

Yes

amRNA by RT-PCR in SON punches (Shibuya et al., 1999): *mRNA for P2X6 was detected (Shibuya et al., 1999); however, in expression systems, ATP induces only very small or undetectable currents via these subtypes. mRNA expression was most prominent for P2X3, 4 and 7.

Ca imaging in isolated SON neurons (Shibuya et al., 1999).

cCa + + imaging of isolated nerve terminals from neural lobe (NL; Troadec et al., 1998). Intracellular electrophysiological recordings from HNS explants (Hiruma and Bourque, 1995).

eBrilliant blue G (BBG), a selective P2X7-R antagonist at 30 |M, inhibited AMPA-R insertion in magnocellular neurons (Gordon et al., amRNA by RT-PCR in SON punches (Shibuya et al., 1999): *mRNA for P2X6 was detected (Shibuya et al., 1999); however, in expression systems, ATP induces only very small or undetectable currents via these subtypes. mRNA expression was most prominent for P2X3, 4 and 7.

Ca imaging in isolated SON neurons (Shibuya et al., 1999).

cCa + + imaging of isolated nerve terminals from neural lobe (NL; Troadec et al., 1998). Intracellular electrophysiological recordings from HNS explants (Hiruma and Bourque, 1995).

eBrilliant blue G (BBG), a selective P2X7-R antagonist at 30 |M, inhibited AMPA-R insertion in magnocellular neurons (Gordon et al., d

Fig. 5. Effect of 10 mM PPADS on AVP response to ATP (A) and ATP + PE. PPADS blocked the transient response induced by ATP alone (A) as well as the sustained response induced by ATP + PE (B). Adapted with permission from Kapoor and Sladek (2000).

increase in [Ca + + ]i that accounted for 80% of the response to a cocktail of P2Y-R agonists (Fig. 6; Song et al., 2007). The role of P2Y-Rs in ATP stimulation of AVP/OTX release and the synergistic response to ATP+PE remains to be assessed.

Receptor signalling cascades activated by ATP+PE: role of [Ca++]t

Having demonstrated that P2X-Rs are required for the ATP+PE synergistic stimulation of AVP/ OTX, we hypothesized that the ATP+PE syner-gism might reflect convergence of the intracellular signalling cascades triggered by ATP-initiated opening of P2X-gated ion channels and PE activation of the Gq/11 a1-Rs. As shown in Fig. 7, both pathways increase [Ca+ + ]i, but via different pathways: one (P2X-R) by allowing influx of extracellular Ca + + and the other (a1-R) by initiating IP3-dependent release of Ca + + from intracellular stores. This convergence might augment elevated [Ca+ + ]i which, in turn, might recruit additional Ca+ +-sensitive mechanisms. We were able to use AVP release from HNS explants as an end point to demonstrate that two components of the a1-R activated Gq/ll signalling cascade, release of Ca + + from intracellular stores and activation of protein kinase C (PKC), are required for the augmented and sustained increase in AVP release induced by ATP + PE (Kapoor and Sladek, 2000; Song et al., 2006). As shown in Fig. 8, pretreatment of HNS explants with TG to deplete intracellular Ca + + stores or the PKC inhibitor, bisindolylma-leimide, prevented ATP + PE-induced AVP release. Furthermore, inhibition of new gene expression by actinomycin also prevented the synergistic stimulation of AVP release by ATP + PE (Kapoor and Sladek, 2000). Thus, an augmented Ca + + signal may activate transcription factors resulting in up-regulation of specific genes. In order to directly evaluate the hypothesis that exposure to ATP + PE results in augmentation of the Ca + + signal, we directly monitored [Ca + + ]i in SON neurons using HNS explants loaded with the Ca ++-sensitive dye, Fura-2AM. As shown in Fig. 9, Fura-2-loaded SON neurons are readily located and visualized from the ventral surface of HNS explants following incubation with Fura-2AM (see Song et al., 2006 for details). ATP, PE and ATP + PE, all caused the expected increase in [Ca + + ]i (Fig. 9B), but the elevation in [Ca + + ]i was extended in response to

  1. 6. A prominent Ca++ response is elicited in SON neurons by a cocktail of P2Y-R agonists (2-MethylS-ADP, 100 mM; UTP, 1 mM; and UDP, 1 mM) and by 2-MeS-ADP alone (a selective P2Y1-R agonist). 2-MeS-ADP is equally effective in the presence of TTX (to block action potential generation) and accounts for 80% of the response to P2Y-R activation. Adapted with permission from Song et al. (2007).
  2. 6. A prominent Ca++ response is elicited in SON neurons by a cocktail of P2Y-R agonists (2-MethylS-ADP, 100 mM; UTP, 1 mM; and UDP, 1 mM) and by 2-MeS-ADP alone (a selective P2Y1-R agonist). 2-MeS-ADP is equally effective in the presence of TTX (to block action potential generation) and accounts for 80% of the response to P2Y-R activation. Adapted with permission from Song et al. (2007).

Fig. 7. Intracellular signal cascades initiated by activation of a1-receptor (1) and P2X-receptor (2). As a Gq/11-coupled receptor, activation of a1-Rs activates protein lipase C (PLC) leading to production of inositol triphosphate (IP3) which stimulates release of Ca++ from intracellular stores (3). Opening of the P2X-gated ion channel allows influx of extracellular Na+ and Ca++ (3). Depolarization initiated by Na+ influx opens voltage-sensitive Ca++ channels (L-type) resulting in further augmentation of [Ca+ + ]i

  • 3). Convergence of these cascades on [Ca+ + ]i could recruit or enhance Ca+ +-sensitive kinases resulting in phosphorylation of proteins
  • 4) potentially resulting in altered receptor trafficking (desensitization) and/or gene expression (5). Adapted with permission from Kapoor and Sladek (2000).

Fig. 7. Intracellular signal cascades initiated by activation of a1-receptor (1) and P2X-receptor (2). As a Gq/11-coupled receptor, activation of a1-Rs activates protein lipase C (PLC) leading to production of inositol triphosphate (IP3) which stimulates release of Ca++ from intracellular stores (3). Opening of the P2X-gated ion channel allows influx of extracellular Na+ and Ca++ (3). Depolarization initiated by Na+ influx opens voltage-sensitive Ca++ channels (L-type) resulting in further augmentation of [Ca+ + ]i

  • 3). Convergence of these cascades on [Ca+ + ]i could recruit or enhance Ca+ +-sensitive kinases resulting in phosphorylation of proteins
  • 4) potentially resulting in altered receptor trafficking (desensitization) and/or gene expression (5). Adapted with permission from Kapoor and Sladek (2000).
  1. 8. The synergistic stimulation of AVP release by ATP + PE requires Ca++ release from internal stores (A), activation of PKC (B) and new gene expression (C). (A) Pretreatment with TG to deplete intracellular Ca++ stores prevented the prolonged and augmented stimulation of AVP release by ATP + PE. Note that DMSO was used as the vehicle for TG. Its presence in both groups during the 30-min exposure to TG increased the osmolality of the perifusate, resulting in the expected stimulation of AVP release. This effect was reversed, following the washout of DMSO and TG. Adapted with permission from Song et al. (2006). (B) The PKC inhibitory, bisindolylmaleimide (bi), prevented the synergistic stimulation of AVP release by ATP + PE. (C) Treatment with actinomycin to block gene transcription prevented the sustained component of ATP + PE stimulation of AVP release, but not the initial transient portion of the response. Adapted with permission from Kapoor and Sladek (2000).
  2. 8. The synergistic stimulation of AVP release by ATP + PE requires Ca++ release from internal stores (A), activation of PKC (B) and new gene expression (C). (A) Pretreatment with TG to deplete intracellular Ca++ stores prevented the prolonged and augmented stimulation of AVP release by ATP + PE. Note that DMSO was used as the vehicle for TG. Its presence in both groups during the 30-min exposure to TG increased the osmolality of the perifusate, resulting in the expected stimulation of AVP release. This effect was reversed, following the washout of DMSO and TG. Adapted with permission from Song et al. (2006). (B) The PKC inhibitory, bisindolylmaleimide (bi), prevented the synergistic stimulation of AVP release by ATP + PE. (C) Treatment with actinomycin to block gene transcription prevented the sustained component of ATP + PE stimulation of AVP release, but not the initial transient portion of the response. Adapted with permission from Kapoor and Sladek (2000).

ATP + PE (Song et al., 2006). Cells remained responsive to other stimuli, following washout of the ATP + PE (Song et al., 2006). Thus, the extended elevation in [Ca + + ]i did not reflect cell dysfunction. Some of the imaged neurons were subsequently identified as AVP neurons based on mounting an increase in [Ca+ + ]i in response to AVP (Dayanithi et al., 1996; Song et al., 2006).

  1. 9. (A) Fura-2-loaded SON neurons in an HNS explant preparation. (B) Live cell Ca+ + imaging in Fura-2-loaded SON neurons. [Ca++]i was increased by exposure to ATP, PE and ATP + PE (peak ratio). [Ca++] remained significantly elevated at the end of the approximately 4-min recording period (end ratio) following ATP + PE exposure compared to either agent alone (p<0.001). Adapted with permission from Song et al. (2006). (See Color Plate 9.9 in color plate section.)
  2. 9. (A) Fura-2-loaded SON neurons in an HNS explant preparation. (B) Live cell Ca+ + imaging in Fura-2-loaded SON neurons. [Ca++]i was increased by exposure to ATP, PE and ATP + PE (peak ratio). [Ca++] remained significantly elevated at the end of the approximately 4-min recording period (end ratio) following ATP + PE exposure compared to either agent alone (p<0.001). Adapted with permission from Song et al. (2006). (See Color Plate 9.9 in color plate section.)

These observations confirmed our hypothesis that activation of multiple mechanisms for increasing [Ca++]i results in a greater Ca++ signal for modulation of Ca+ +-sensitive cellular mechanisms. This altered Ca++ signal might activate Ca++-

sensitive kinases resulting in phosphorylation of transcription factors to drive a change in gene expression, phosphorylation of receptors to alter desensitization characteristics or phosphorylation of other cellular proteins required for secretion.

Remaining issues and new hypotheses What genes are regulated?

Since a shift from a transient response to ATP or PE alone to a sustained response is a hallmark of the ATP + PE synergism, and since P2X-R subtypes differ in their desensitization characteristics (Table 1), the P2X-R subtypes are interesting candidates for mediating the ATP+PE-induced shift from transient to sustained hormone release. Specifically, formation of P2X2/3 heterodimers could convert a transient response to ATP alone, mediated by either the slowly desensitizing P2X2-R or the rapidly desensitizing P2X3-R to one that does not desensitize. The sensitivity of both the ATP and ATP + PE responses to PPADS is consistent with this hypothesis, as well as the ability of suramin to block the activation of AVP neurons by moderate haemorrhage (Buller et al., 1996). Formation of heterodimers could be induced by increasing the number of either P2X2-R or P2X3-R subunits available. Thus, an increase in expression of one of these genes could alter the response to ATP. The requirement for PKC might reflect phosphorylation of P2X2-R subunits as this has been shown to modulate desensitization (Boue-Grabot et al., 2000).

P2X7-Rs are also interesting candidates for mediating a sustained response to ATP. They have been shown to alter synaptic function in SON (Gordon et al., 2005), are non-desensitizing and their activation by extended exposure to ATP results in formation of a pore large enough to flux molecules up to 900 Da (Table 1; North, 2002). Thus, pore formation can result in efflux or influx of small molecules such as nucleotides, glutamate and other neuroactive amino acids, serotonin and even small peptides. Since P2X7-Rs are not blocked by the concentration of PPADS that was effective in our experiments (10 mM), they cannot account for the full response to ATP in SON neurons. Involvement of P2X7-Rs in the sustained response to ATP + PE would require a switch in the P2X-R subtype responsible for initiating and sustaining the response. This possibility is supported by the observation that the sustained elevation in [Ca + + ]; did not require continued presence of ATP + PE (Song et al., 2006). Thus, an initial augmentation of the [Ca + + ]; signal can be postulated to be the signal that precipitates a change in gene transcription that subsequently leads to an augmented and sustained response to ATP. This possibility is supported by the delay in the augmented and sustained component of the response to ATP + PE (Fig. 1). However, a change in P2X-R gene expression is only one of many possibilities that might promote extended AVP/ OTX responses. Subtypes of a1-R also differ in their rate of internalization (Chalothorn et al., 2002), and therefore a shift in the subtype of a1-R involved can similarly be postulated as a mechanism for the shift to a sustained response. Induction of the AVP and OTX genes might also participate, but due to the large hormone stores in the neural lobe, this is unlikely to be a prerequisite for sustained release in the time frame of our experiments. However, it may be important in pathological conditions associated with attenuation of AVP secretion resulting in shock (Oliver and Landry, 2007).

Are P2Y-Rs important for the synergistic response?

The finding that PPADS at a concentration that is selective for P2X receptors blocked ATP + PE-induced synergistic stimulation of AVP and OTX release from HNS explants demonstrates that activation of P2X receptors are required for the effect, but it does not eliminate the possibility that the P2Y receptors, which we subsequently demonstrated in SON, are also required (i.e. P2X-Rs are required, but may not be sufficient to induce synergism). Since P2Y-Rs are Gq/11-coupled receptors, their activation by ATP in SON neurons raises the question about their importance versus the a1-Rs, because both are coupled to Gq/11 and both induce release of Ca + + from internal stores. Perhaps the observed augmentation requires activation of multiple Gq/11-Rs or perhaps the receptors differ with respect to coupling to non-Gq-mediated signalling cascades [e.g. Gpy, RhoA, MAPK/Erk, etc. (Hubbard and Hepler, 2006)]. P2Y-Rs have been associated with activation of MAPKs, PI3k, Akt and Ca+ +-independent signalling cascades including P2Y1-R-mediated phosphorylation of ERK1/2

(May et al., 2006; Tran and Neary, 2006). Thus, evaluation of the role of P2Y-Rs in ATP + PE-induced synergism is important.

What is the physiological significance of the synergistic effect of ATP+PE?

Successful maintenance of cardiovascular homeo-stasis requires that the systems designed to maintain blood pressure have the capacity to respond to both acute decreases in blood return to the heart (e.g. orthostatic changes) and chronic conditions such as haemorrhage or dehydration. AVP is important in both situations due to its potent vasoconstrictor and antidiuretic actions. Thus, it is desirable to have mechanisms that allow for large and rapid increases in blood pressure in response to postural changes (moving from lying or sitting to standing) as well as sustained responses that can allow for fluid replacement. Very large, but transient increases in plasma AVP secretion occur throughout daily activity (Katz et al., 1979). In contrast, following haemorrhage, large and sustained elevations in plasma AVP are required to prevent cardiovascular collapse. The failure to maintain elevated plasma AVP is associated with the development of shock following haemorrhage and in other vasodilatory conditions (Oliver and Landry, 2007). The transition from transient AVP responses to ATP and PE alone to sustained AVP responses to ATP + PE described herein may underlie these important characteristics of AVP secretion in response to acute and chronic hypotension and hypovolemia. Identification of the receptors and cellular mechanisms underlying this transition will provide the information necessary to evaluate the importance of this phenomenon to cardiovascular homeostasis.

Acknowledgements

This work was supported by a grant from the National Institutes of Health (R01 NS 27975 to CDS). The authors are grateful for the exceptional technical contributions of Ms. Wanida Stevens.

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I.D. Neumann and R. Landgraf (Eds.) Progress in Brain Research, Vol. 170 ISSN 0079-6123

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