The hippocampal area (CA) CA2 is important for social interaction and is innervated by Substance P (SP)-expressing supramammillary (SuM) nucleus neurons. SP exerts neuromodulatory effects on pain processing and central synaptic transmission. Here we provide evidence that SP can induce a slowly developing NMDA receptor- and protein synthesis-dependent potentiation of synaptic transmission that can be induced not only at entorhinal cortical (EC)-CA2 synapses but also at long-term potentiation (LTP)-resistant Schaffer collateral (SC)-CA2 synapses. In addition, SP-induced potentiation of SC-CA2 synapses transforms a short-term potentiation of EC-CA2 synaptic transmission into LTP, consistent with the synaptic tagging and capture hypothesis. Interestingly, this SP-induced potentiation and associative interaction between the EC and SC inputs of CA2 neurons is independent of the GABAergic system. In addition, CaMKIV and PKMζ play a critical role in the SP-induced effects on SC-CA2 and EC-CA2 synapses. Thus, afferents from SuM neurons are ideally situated to prime CA2 synapses for the formation of long-lasting plasticity and associativity.
Hepatitis B virus (HBV) infection remains a major issue among dialysis patients. It is associated with a high risk of hepatic complication. The liver disease runs a unique clinical course in dialysis patients, as it can progress with modest hepatic inflammation and prominent fibrosis. The conventional cut-off level of serum alanine aminotransferase (ALT) for commencing antiviral therapy may prove too high and inappropriate for dialysis patients, and liver biopsy appears to be the only definitive means to establish the activity of liver disease in dialysis patients. Liver biopsy should be considered in patients with a serum ALT level that is persistently greater than 30 IU/L, or 0.75-fold the upper limit of the normal level, and/or other clinical and laboratory findings that suggest active liver disease. For antiviral treatment, preliminary reports have shown that lamivudine is effective and well tolerated in dialysis patients. However, the long-term efficacy of lamivudine and its optimal effective dose in dialysis patients remain unknown. The prevention of nosocomial transmission among dialysis patients is also important. Universal precaution measures should be strictly observed and the segregation of hepatitis B surface antigenpositive hemodialysis patients should be considered. For HBV non-immune patients, the importance of HBV vaccination should not be overemphasized. Until a new generation of highly immunogenic vaccines that are proven to be safe and effective in patients with end-stage renal disease becomes available, early vaccination before the development of end-stage renal failure remains the best way to secure immunological protection against HBV infection in dialysis patients.
Alternative splicing changes the Ca1.2 calcium channel electrophysiological property, but the in vivo significance of such altered channel function is lacking. Structure-function studies of heterologously expressed Ca1.2 channels could not recapitulate channel function in the native milieu of the cardiomyocyte. To address this gap in knowledge, we investigated the role of alternative exon 33 of the Ca1.2 calcium channel in heart function. Exclusion of exon 33 in Ca1.2 channels has been reported to shift the activation potential -10.4 mV to the hyperpolarized direction, and increased expression of Ca1.2 channels was observed in rat myocardial infarcted hearts. However, how a change in Ca1.2 channel electrophysiological property, due to alternative splicing, might affect cardiac function in vivo is unknown. To address these questions, we generated m exon 33-null mice. These mice contained Ca1.2 channels with a gain-of-function that included conduction of larger currents that reflects a shift in voltage dependence and a modest increase in single-channel open probability. This altered channel property underscored the development of ventricular arrhythmia, which is reflected in significantly more deaths of exon 33 mice from β-adrenergic stimulation. In vivo telemetric recordings also confirmed increased frequencies in premature ventricular contractions, tachycardia, and lengthened QT interval. Taken together, the significant decrease or absence of exon 33-containing Ca1.2 channels is potentially proarrhythmic in the heart. Of clinical relevance, human ischemic and dilated cardiomyopathy hearts showed increased inclusion of exon 33. However, the possible role that inclusion of exon 33 in Ca1.2 channels may play in the pathogenesis of human heart failure remains unclear.
Rationale: Ca V 1.2 channels are essential for excitation-contraction coupling in the cardiovascular system, and alternative splicing optimizes its role. Galectin-1 (Gal-1) has been reported to regulate vascular smooth muscle cell (VSMC) function and play a role in pulmonary hypertension. We have identified Gal-1 multiple times in yeast 2-hybrid assays using the Ca V 1.2 I-II loop as bait.Objective: Our hypothesis is that Gal-1 interacts directly with Ca V 1.2 channel at the I-II loop to affect arterial constriction. Methods and Results:Unexpectedly, Gal-1 was found to selectively bind to the I-II loop only in the absence of alternatively spliced exon 9*. We found that the current densities of Ca V 1.2 ⌬9* channels were significantly inhibited as a result of decreased functional surface expression due to the binding of Gal-1 at the export signal located on the C-terminus of exon 9. Moreover, the suppression of Gal-1 expression by siRNA in rat A7r5 and isolated VSMCs produced the opposite effect of increased I Ca,L . The physiological significance of Gal-1 mediated splice variant-specific inhibition of Ca V 1.2 channels was demonstrated in organ bath culture where rat MAs were reversibly permeabilized with Gal-1 siRNA and the arterial wall exhibited increased K ؉ -induced constriction. Key Words: Ca V 1.2 Ⅲ galectin-1 Ⅲ vascular smooth muscle cell Ⅲ arterial constriction T he Ca V 1.2 L-type calcium channels (LTCCs) are the primary conduits for Ca 2ϩ influx that lead to initiation of numerous physiological processes, including muscle excitation-contraction coupling, neurotransmitter release, gene expression, and hormone secretion. Under optimal conditions, Ca 2ϩ influx through the activated Ca V 1.2 channels in the vascular smooth muscle cells (VSMCs) tightly influences the contractility of small arteries and arterioles, and maintains the myogenic tone of resistance vessels. 1,2 However, if this process goes awry during the pathogenesis of hypertension, an increase in Ca 2ϩ influx may contribute to the development of an abnormal vascular tone and result in elevated peripheral vascular resistance. 3,4 Of the 4 subunits (␣ 1 , , ␣2/␦, and ␥) that composed the calcium channels, the Ca V ␣ 1 subunit not only forms the aqueous pore but also possesses the voltage sensor, gating apparatus and sites for channel regulation by second messengers, drugs, and toxins. 5,6 Within the intracellular linker region between homologous domains I and II of ␣ 1 subunit (I-II loop) is the ␣ 1 -subunit interaction domain (AID), a site where the auxiliary Ca V  subunit binds to traffic ␣ 1 subunit to cell membrane. 7 Moreover, alternative splicing at the Ca V 1.2 I-II loop produces a subpopulation of Ca V 1.2 channel splice variant that contain exon 9*, which is important for vasotone maintenance in blood vessels ( Figure 1A). 8 -11 To date, we and others have identified and characterized 3 predominant Ca V 1.2 splice combinations that are found in arterial smooth muscles, namely, Ca V 1.2 77WT (1-8-⌬9*-33), Ca V 1.2 SM (1-8-9*-⌬33),...
We have defined molecularly that Gal-1 promotes Ca1.2 degradation by replacing Caβ and thereby exposing specific lysines for polyubiquitination and by masking I-II loop endoplasmic reticulum export signals. This mechanistic understanding provided the basis for targeting Ca1.2-Gal-1 interaction to demonstrate clearly the modulatory role that Gal-1 plays in regulating blood pressure, and offering a potential approach for therapeutic management of hypertension.
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