Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:4.6.1.1 (adenylate cyclase)
 19,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The temperature-dependence of the actions of beta-receptor agonists and adenylate cyclase stimulation on both calcium and delayed rectifier potassium channel ionic currents were examined in patch-clamped guinea pig ventricular myocytes. We report that temperature can separate the beta-receptor mediated modulation of potassium and calcium channels. Receptor-mediated increases in the delayed rectifier potassium current, but not the calcium current were very temperature-dependent over the range of 19 to 32 degrees C. At room temperature (19-22 degrees C) the beta-agonist isoproterenol produced a large enhancement of the calcium current but had no effect on the delayed rectifier current. In contrast, at warmer temperatures (28-32 degrees C) both currents increased in the presence of the agonist. This temperature-sensitivity also existed for direct stimulation of adenylate cyclase by forskolin. Thus, cardiac calcium and potassium channels appear to be independently regulated during adrenergic stimulation.
 ...
PMID:Beta-adrenergic modulation in the heart. Independent regulation of K and Ca channels. 245 8

beta-Adrenergic stimulation of ventricular heart cells results in the enhancement of two important ion currents that regulate the plateau phase of the action potential: the delayed rectifier potassium channel current (IK) and L-type calcium channel current (ICa). The temperature dependence of beta-adrenergic modulation of these two currents was examined in patch-clamped guinea pig ventricular myocytes at various steps in the beta-receptor/cyclic AMP-dependent protein kinase pathway. External applications of isoproterenol and forskolin were used to activate the beta-receptor and the enzyme adenylate cyclase, respectively. Internal dialysis of cyclic 3',5'-adenosine monophosphate (cAMP) or the catalytic subunit of cAMP-dependent protein kinase (CS), as well as the external addition of 8-chlorphenylthio cAMP (CPT-cAMP) was applied to increase intracellular levels of cAMP and CS. Isoproterenol-mediated increases in IK, but not ICa, were found to be very temperature dependent over the range of 20-37 degrees C. At room temperature (20-22 degrees C) isoproterenol produced a large (threefold) enhancement of ICa but had no effect on IK. In contrast, at warmer temperatures (30-37 degrees C) both currents increased in the presence of this agonist and the kinetics of IK were slowed at -30 mV. A similar temperature sensitivity also existed after exposure to forskolin, CPT-cAMP, cAMP, and CS, suggesting that this temperature sensitivity of IK may arise at the channel protein level. Modulation of IK during each of these interventions was accompanied by a slowing in IK kinetics. Thus, regulation of cardiac potassium channels but not calcium channels involves a temperature-dependent step that occurs after activation of the catalytic subunit of cAMP-dependent protein kinase.
 ...
PMID:Beta-adrenergic modulation of cardiac ion channels. Differential temperature sensitivity of potassium and calcium currents. 247 62

In the cochlea, K+ is secreted by electrodiffusion across the apical membrane of strial marginal cells via the IsK/KvLQT1 ('IsK') channel. This channel complex has been reported to be activated in other systems by adenosine 3',5'-cyclic monophosphate (cAMP). Since several reports had suggested that cAMP is a second messenger in the cochlea, the effect of the cAMP pathway on transepithelial K+ secretion by strial marginal cells of the gerbil was studied. Both the transepithelial current (Isc) and K+ flux (JK) across strial marginal cell epithelium were measured; Isc in a micro-Ussing chamber and JK as the gradient of K+ concentration near the apical membrane. The apical membrane current (IIsK) and conductance (gIsK) of IsK channels were recorded with the on-cell macro-patch and the nystatin-perforated whole-cell patch clamp techniques. It has previously been shown that the apical IsK channel constitutes the primary pathway for K+ secretion. Cytoplasmic cAMP was elevated by applying dibutyryl cyclic-AMP (dbcAMP) or the phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine (IBMX) at 37 degrees C. dbcAMP (1 mM) increased Isc by 51 +/- 4% and IIsK in on-cell and whole-cell recordings increased by 214 +/- 63% and 390 +/- 61% above the control value, respectively. IBMX (1 mM) caused transient increases of Isc by 53 +/- 3% and IIsK in on-cell recordings by 177 +/- 75% above the control value. The leak conductance due to all non-IsK channel sources did not change in the presence of dbcAMP or IBMX. dbcAMP (1 mM at 24 degrees C) increased JK by 53 +/- 16% and Isc by 18 +/- 4%. IBMX (1 mM at 24 degrees C) had no effect, suggesting reduced activity of adenylate cyclase at this temperature. Our results demonstrate that the cAMP pathway is constitutively active in strial marginal cells and that the cAMP pathway stimulates transepithelial K+ secretion by increasing IsK channel current rather than by altering another transport pathway.
 ...
PMID:cAMP increases K+ secretion via activation of apical IsK/KvLQT1 channels in strial marginal cells. 944 25

Lethal cardiac arrhythmias are a hallmark of the hereditary Long QT syndrome (LQTS), a disease produced by mutations of cardiac ion channels [1]. Often these arrhythmias are stress-induced, suggesting a relationship between beta-adrenergic activation of adenylate cyclase and cAMP-dependent alteration of one or more of the ion channels involved in LQTS. Second messengers modulate ion channel activity either by direct interaction or through intermediary kinases and phosphatases. Here we show that the second messenger cAMP regulates the K(+) channel mutated in the LQT2 form of LQTS, HERG [2], both directly and indirectly. Activation of cAMP-dependent protein kinase (PKA) causes phosphorylation of HERG accompanied by a rapid reduction in current amplitude, acceleration of voltage-dependent deactivation, and depolarizing shift in voltage-dependent activation. In a parallel pathway, cAMP directly binds to the HERG protein with the opposing effect of a hyperpolarizing shift in voltage-dependent activation. The summation of cAMP-mediated effects is a net diminution of the effective current, but when HERG is complexed with with the K(+) channel accessory proteins MiRP1 or minK, the stimulatory effects of cAMP are favored. These findings provide a direct link between stress and arrhythmia by a unique mechanism where a single second messenger exerts complex regulation of an ion channel via two distinct pathways.
 ...
PMID:Cyclic AMP regulates the HERG K(+) channel by dual pathways. 1083 51