Okadaic Acid-Sensitive Protein Phosphatases Constrain Phrenic Long-Term Facilitation after Sustained Hypoxia

Abstract

Phrenic long-term facilitation (pLTF) is a serotonin-dependent form of pattern-sensitive respiratory plasticity induced by intermittent hypoxia (IH), but not sustained hypoxia (SH). The mechanism(s) underlying pLTF pattern sensitivity are unknown. SH and IH may differentially regulate serine/threonine protein phosphatase activity, thereby inhibiting relevant protein phosphatases uniquely during IH and conferring pattern sensitivity to pLTF. We hypothesized that spinal protein phosphatase inhibition would relieve this braking action of protein phosphatases, thereby revealing pLTF after SH. Anesthetized rats received intrathecal (C4) okadaic acid (25 nM) before SH (25 min, 11% O 2 ). Unlike (vehicle) control rats, SH induced a significant pLTF in okadaic acid-treated rats that was indistinguishable from rats exposed to IH (three 5 min episodes, 11% O 2 ). IH and SH with okadaic acid may elicit pLTF by similar, serotonin-dependent mechanisms, because intravenous methysergide blocks pLTF in rats receiving IH or okadaic acid plus SH. Okadaic acid did not alter IH-induced pLTF. In summary, pattern sensitivity in pLTF may reflect differential regulation of okadaic acid-sensitive serine/threonine phosphatases; presumably, these phosphatases are less active during/after IH versus SH. The specific okadaic acid-sensitive phosphatase(s) constraining pLTF and their spatiotemporal dynamics during and/or after IH and SH remain to be determined.

Phrenic Motoneuron Discharge Patterns During Hypoxia-Induced Short-Term Potentiation in Rats

“…Decreases in arterial pH during hypoxia have been reported previously (Golder and Martinez 2008;Iizuka and Fregosi 2007), possibly reflecting an increase in plasma lactate concentration (Romeh and Tannen 1986). Mean arterial blood pressure (MAP) was reduced during hypoxia (P Ͻ 0.01; Table 2) as previously reported (Bavis and Mitchell 2003;Fuller 2005;Wilkerson et al 2008). However, MAP returned to baseline values by 3 min after hypoxia (Table 2).…”

Neither serotonin nor adenosine-dependent mechanisms preserve ventilatory capacity in ALS rats

“…NADPH oxidase activity is necessary for AIH-induced pLTF (MacFarlane and Mitchell, 2007; MacFarlane and Mitchell, 2008a; MacFarlane and Mitchell, 2009; MacFarlane et al 2009). Since pLTF is constrained by okadaic acid sensitive serine/threonine protein phosphatases (Wilkerson et al 2008), we suggested that NADPH derived ROS inhibit these phosphatases, thereby enabling full pLTF expression. When spinal phosphatases are inhibited with okadaic acid, AIH-induced pLTF is restored in rats pretreated with ROS scavengers (MacFarlane et al 2008).…”

Repetitive acute intermittent hypoxia increases expression of proteins associated with plasticity in the phrenic motor nucleus

“…the “Q pathway;” Dale-Nagle et al, 2010) include greater serotonin terminal density, and 5-HT 2A receptor, BDNF, TrkB and phospho-ERK expression. We anticipate interesting changes in the expression of other proteins known to play key roles in AIH-induced respiratory plasticity, such as protein kinase C (Devinney and Mitchell, unpublished), serine/threonine protein phosphatases (Wilkerson et al, 2008) and NADPH oxidase (MacFarlane et al, 2009). …”

“…AIH-induced pLTF is enhanced by prior experience with intermittent hypoxia (Ling et al, 2001; Mitchell et al, 2001; Wilkerson et al, 2008). For example, pretreatment with chronic intermittent hypoxia (CIH) enhances pLTF during anesthesia (Ling et al, 2001) and ventilatory LTF in unanesthetized rats (McGuire et al, 2003).…”