T-type Ca2+ channels and their relationship with pre-neoplastic and neoplastic lesions in the human breast

The expression of T-type voltage-dependent Ca2+ channels (Cav3) has been previously observed in breast cancer, but their expression and subcellular localization were not evaluated in pre-neoplastic lesions. Therefore, this work aimed to evaluate protein expression and subcellular localization of T-type channel isoforms in human breast tissue samples. Protein expressions of CaV3.1, CaV3.2, and CaV3.3 were evaluated by immunohistochemistry in breast without alteration, in proliferative non-neoplastic lesions, and in neoplastic ductal epithelial lesions of the human breast. CaV3.1, CaV3.2, and CaV3.3 nuclear expressions were decreased in advanced stages of neoplastic transformation, whereas CaV3.1 and CaV3.2 cytoplasmic expression increased. Also, the decrease in nuclear expression was correlated with an increase in cytoplasmic expression for CaV3.1 isoform. The change in CaV3 protein expression and subcellular localization are consistent with the neoplastic transformation stages of mammary epithelial cells, evident in early neoplastic lesions, such as ductal carcinomas in situ. These results suggest a possible involvement of CaV3 in the carcinogenic processes and could be considered as a potential pharmacological target in new therapies for breast cancer treatment.

Chronic Ca²⁺ influx through voltage-dependent Ca²⁺ channels enhance delayed rectifier K⁺ currents via activating Src family tyrosine kinase in rat hippocampal neurons

Excessive influx and the subsequent rapid cytosolic elevation of Ca²⁺ in neurons is the major cause to induce hyperexcitability and irreversible cell damage although it is an essential ion for cellular signalings. Therefore, most neurons exhibit several cellular mechanisms to homeostatically regulate cytosolic Ca²⁺ level in normal as well as pathological conditions. Delayed rectifier K⁺ channels (I(DR) channels) play a role to suppress membrane excitability by inducing K⁺ outflow in various conditions, indicating their potential role in preventing pathogenic conditions and cell damage under Ca²⁺-mediated excitotoxic conditions. In the present study, we electrophysiologically evaluated the response of IDR channels to hyperexcitable conditions induced by high Ca²⁺ pretreatment (3.6 mM, for 24 hours) in cultured hippocampal neurons. In results, high Ca²⁺-treatment significantly increased the amplitude of IDR without changes of gating kinetics. Nimodipine but not APV blocked Ca²⁺-induced IDR enhancement, confirming that the change of I(DR) might be targeted by Ca²⁺ influx through voltage-dependent Ca²⁺ channels (VDCCs) rather than NMDA receptors (NMDARs). The VDCC-mediated I(DR) enhancement was not affected by either Ca²⁺-induced Ca²⁺ release (CICR) or small conductance Ca²⁺-activated K⁺ channels (SK channels). Furthermore, PP2 but not H89 completely abolished I(DR) enhancement under high Ca²⁺ condition, indicating that the activation of Src family tyrosine kinases (SFKs) is required for Ca²⁺-mediated I(DR) enhancement. Thus, SFKs may be sensitive to excessive Ca²⁺ influx through VDCCs and enhance I(DR) to activate a neuroprotective mechanism against Ca²⁺-mediated hyperexcitability in neurons.

Effects of pH on Vascular Tone in Rabbit Basilar Arteries

Effects of pH on vascular tone and L-type Ca2+ channels were investigated using Mulvany myograph and voltage-clamp technique in rabbit basilar arteries. In rabbitbasilar arteries, high K+ produced tonic contractions by 11+/-0.6 mN (mean+/-S.E., n=19). When extracellular pH (pHo) was changed from control 7.4 to 7.9 ([alkalosis]o), K+-induced contraction was increased to 128+/-2.1% of the control (n=13). However, K+-induced contraction was decreased to 73+/-1.3% of the control at pHo 6.8 ([acidosis]o, n=4). Histamine (10 micrometer) also produced tonic contraction by 11+/-0.6 mN (n=17), which was blocked by post-application of nicardipine (1 micrometer). [alkalosis]o and [acidosis]o increased or decreased histamine-induced contraction to 134+/-5.7% and 27+/-7.6% of the control (n=4, 6). Since high K+- and histamine-induced tonic contractions were affected by nicardipine and pHo, the effect of pHo on voltage-dependent L-type Ca2+ channel (VDCCL) was studied. VDCCL was modulated by pHo: the peak value of Ca2+ channel current (IBa) at a holding of 0 mV decreased in [acidosis]o by 41+/-8.8%, whereas that increased in [alkalosis]o by 35+/-2.1% (n=3). These results suggested that the external pH regulates vascular tone partly via the modulation of VDCC in rabbit basilar arteries.

Effect of theaflavin on intracellular free calcium concentration in rat ventricular myocytes / 中国药理学通报

Aim To observe the effects of theaflavin on intracellular calcium concentration(i) level in rat ventricular myocytes and discuss the possible mechanisms.Methods The effects of theaflavin oni were investigated in rat ventricular myocytes.i was detected by laser confocal microscopy and represented by relative fluorescent intensity(FI-FI0)/FI0,%;FI0:control;FI:administration of drugs).Results ① Theaflavin(10,20,40 ?mol?L-1) had no effect on the i of ventricular myocytes in normal Tyrode′s solution.However,it reduced the i of ventricular myocytes in simulated ischemia solution in a concentration-dependent manner.② Pretreatment with Bay k8644(0.5 ?mol?L-1) mostly abolished the effects of theaflavin(20 ?mol?L-1) in simulated ischemia solution.③ Theaflavin(20 ?mol?L-1) markedly inhibited the low concentration of ryanodine-induced i increase in Ca2+-free Tyrode′s solution.④ When the propagating waves of elevated i(Ca2+ waves) were produced by increasing extracellular Ca2+ concentration from 1 mmol?L-1to 10 mmol?L-1,theaflavin(20 ?mol?L-1) could block the propagating waves of elevated i(Ca2+ waves),reduce the frequency and duration of propagating waves,and reduce i as well.Conclusion Theaflavin may reduce the i in isolated rat ventricular myocytes via inhibiting Ca2+ influx by voltage-dependent Ca2+ channel and alleviating Ca2+ release from sarcoplasmic reticulum(SR).

Effects of Rhynchophylline and Isorhynchophylline on the (45)~Ca-transportation in rabbit aorta / 中国药理学通报

The effects of Rhynchophylline (Rhy) and Isorhychophyiline (Isorhy), the alkaloids abstracted from the Chinese traditional herb Uncaria rhynchophyllia (Miq) Jackson, on the 45Ca-influx and efflux were investigated in rabbit aorta. Both Rhy and Isorhy (10 ?mol? L-1) inhibited the 45Ca-influx induced by high K+(77. 0 mmol ? L-1), but neither significant-ly influenced the 45Ca-influx and efflux induced by noradrenaline (10 ?mol ? L-1). The results suggest that these alkaloids block the Voltage-dependent calcium channel.