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      Abnormal coronary function in mice deficient in alpha1H T-type Ca2+ channels.

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      Publication date:
      Journal: Science (New York, N.Y.)
      Keywords: Acetylcholine, pharmacology, Animals, Arteries, drug effects, physiology, Calcium, metabolism, Calcium Channels, T-Type, genetics, Coronary Vessels, pathology, Echocardiography, Electrocardiography, Endothelium, Vascular, Female, Fibrosis, Ganglia, Spinal, cytology, Gene Targeting, Heart, Heart Rate, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Muscle, Smooth, Vascular, Myocardium, Neurons, Nickel, Nitric Oxide, Nitric Oxide Donors, Nitroprusside, Patch-Clamp Techniques, Vasoconstriction, Vasodilation

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          Abstract

          Calcium ion (Ca2+) influx through voltage-gated Ca2+ channels is important for the regulation of vascular tone. Activation of L-type Ca2+ channels initiates muscle contraction; however, the role of T-type Ca2+ channels (T-channels) is not clear. We show that mice deficient in the alpha1H T-type Ca2+ channel (alpha(1)3.2-null) have constitutively constricted coronary arterioles and focal myocardial fibrosis. Coronary arteries isolated from alpha(1)3.2-null arteries showed normal contractile responses, but reduced relaxation in response to acetylcholine and nitroprusside. Furthermore, acute blockade of T-channels with Ni2+ prevented relaxation of wild-type coronary arteries. Thus, Ca2+ influx through alpha1H T-type Ca2+ channels is essential for normal relaxation of coronary arteries.

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          Physiological roles and properties of potassium channels in arterial smooth muscle.

          M T Nelson, J Quayle (1995)
          This review examines the properties and roles of the four types of K+ channels that have been identified in the cell membrane of arterial smooth muscle cells. 1) Voltage-dependent K+ (KV) channels increase their activity with membrane depolarization and are important regulators of smooth muscle membrane potential in response to depolarizing stimuli. 2) Ca(2+)-activated K+ (KCa) channels respond to changes in intracellular Ca2+ to regulate membrane potential and play an important role in the control of myogenic tone in small arteries. 3) Inward rectifier K+ (KIR) channels regulate membrane potential in smooth muscle cells from several types of resistance arteries and may be responsible for external K(+)-induced dilations. 4) ATP-sensitive K+ (KATP) channels respond to changes in cellular metabolism and are targets of a variety of vasodilating stimuli. The main conclusions of this review are: 1) regulation of arterial smooth muscle membrane potential through activation or inhibition of K+ channel activity provides an important mechanism to dilate or constrict arteries; 2) KV, KCa, KIR, and KATP channels serve unique functions in the regulation of arterial smooth muscle membrane potential; and 3) K+ channels integrate a variety of vasoactive signals to dilate or constrict arteries through regulation of the membrane potential in arterial smooth muscle.
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            Congenital deafness and sinoatrial node dysfunction in mice lacking class D L-type Ca2+ channels.

            J Platzer, J. Engel, A Schrott-Fischer … (2000)
            Voltage-gated L-type Ca2+ channels (LTCCs) containing a pore-forming alpha1D subunit (D-LTCCs) are expressed in neurons and neuroendocrine cells. Their relative contribution to total L-type Ca2+ currents and their physiological role and significance as a drug target remain unknown. Therefore, we generated D-LTCC deficient mice (alpha1D-/-) that were viable with no major disturbances of glucose metabolism. alpha1D-/-mice were deaf due to the complete absence of L-type currents in cochlear inner hair cells and degeneration of outer and inner hair cells. In wild-type controls, D-LTCC-mediated currents showed low activation thresholds and slow inactivation kinetics. Electrocardiogram recordings revealed sinoatrial node dysfunction (bradycardia and arrhythmia) in alpha1D-/- mice. We conclude that alpha1D can form LTCCs with negative activation thresholds essential for normal auditory function and control of cardiac pacemaker activity.
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              Functional role of L-type Cav1.3 Ca2+ channels in cardiac pacemaker activity.

              M E Mangoni, B Couette, E Bourinet … (2003)
              The spontaneous activity of pacemaker cells in the sino-atrial node (SAN) controls the heart rhythm and rate under physiological conditions. Pacemaker activity in SAN cells is due to the presence of the diastolic depolarization, a slow depolarization phase that drives the membrane voltage from the end of an action potential to the threshold of a new action potential. SAN cells express a wide array of ionic channels, but we have limited knowledge about their functional role in pacemaker activity and we still do not know which channels play a prominent role in the generation of the diastolic depolarization. It is thus important to provide genetic evidence linking the activity of genes coding for ionic channels to specific alterations of pacemaker activity of SAN cells. Here, we show that target inactivation of the gene coding for alpha(1D) (Ca(v)1.3) Ca(2+) channels in the mouse not only significantly slows pacemaker activity but also promotes spontaneous arrhythmia in SAN pacemaker cells. These alterations of pacemaker activity are linked to abolition of the major component of the L-type current (I(Ca,L)) activating at negative voltages. Pharmacological analysis of I(Ca,L) demonstrates that Ca(v)1.3 gene inactivation specifically abolishes I(Ca,L) in the voltage range corresponding to the diastolic depolarization. Taken together, our data demonstrate that Ca(v)1.3 channels play a major role in the generation of cardiac pacemaker activity by contributing to diastolic depolarization in SAN pacemaker cells.
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                Author and article information

                Journal
                PubMed ID:: 14631046
                DOI:: 10.1126/science.1089268

                ScienceOpen disciplines: Chemistry
                Keywords: Acetylcholine,pharmacology,Animals,Arteries,drug effects,physiology,Calcium,metabolism,Calcium Channels, T-Type,genetics,Coronary Vessels,pathology,Echocardiography,Electrocardiography,Endothelium, Vascular,Female,Fibrosis,Ganglia, Spinal,cytology,Gene Targeting,Heart,Heart Rate,Male,Mice,Mice, Inbred C57BL,Mice, Knockout,Muscle, Smooth, Vascular,Myocardium,Neurons,Nickel,Nitric Oxide,Nitric Oxide Donors,Nitroprusside,Patch-Clamp Techniques,Vasoconstriction,Vasodilation
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                ScienceOpen disciplines: Chemistry
                Keywords: Acetylcholine, pharmacology, Animals, Arteries, drug effects, physiology, Calcium, metabolism, Calcium Channels, T-Type, genetics, Coronary Vessels, pathology, Echocardiography, Electrocardiography, Endothelium, Vascular, Female, Fibrosis, Ganglia, Spinal, cytology, Gene Targeting, Heart, Heart Rate, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Muscle, Smooth, Vascular, Myocardium, Neurons, Nickel, Nitric Oxide, Nitric Oxide Donors, Nitroprusside, Patch-Clamp Techniques, Vasoconstriction, Vasodilation

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