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BIOL 4510 (1)
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York University
BIOL 4510

BIOL4510 / KINE4510 Adrenergic Signaling 2 Peter Backx This section reviews the autonomic nervous system and summarizes the major targets of adrenergic and muscarinic (M2) activaton Autonomic Nervous System A Quick Review Sympathetic and Parasympathetic Innervation of the Heart 1 Targets of -adrenergic signaling Much of the material to follow has already been covered Funny current: Hyperpolarization-activated cation (HCN) channels or I f 2+ L-type Ca channels: I Ca,L, Cav1.2/Cav1.3 2 - forms a macromolecular complex with -adrenergic receptor, adenylate cyclase, PKA, PP2A, G , AKSP 2+ - increase in ICa,L will: 1) activate more clusters leading to larger Ca transients 2) increase the influx of Ca 2+ into the cell which will 2+ also increase the 2+ transient (decrease threshold for Ca release via RYR2 receptors 3) tend to prolong the action potential 4) increases heart rate (lower threshold, increase SR 2+ 2+ Ca thereby increasing spontaneous Ca release and I NCX ) 5) accelerates conduction through the AV node (see below) SERCA2a via Phospholamban and Sarcolipin - Increases SERCA2a activity by reducing PLN and SLN affinity for pump: PLN and SLN monomers are natural inhibitors of SERCA2a - Increases PLN pentamer formation which decreases monomers (mass action) 3 2+ - Allows SER2+2a to better compete with NCX for Ca entering2+ytosol from L-type Ca channels or RYR2 opening thereby placing more Ca into SR. - once Ca 2+ transients rise the NCX is able to compete with SERCA2a for the Ca 2+(SERCA2a is a high affinity low capacity transporter while NCX is a low 2+ affinity high capacity Ca transporter). - Elevated SR Ca 2+increased P fOr RYR2 and spontaneous Ca 2+ release - Elevated SR Ca 2+increases the amount of Ca 2+ released by each couplon cluster of RYR2 2+ 2+ - Elevated SR Ca increased spontaneous Ca release and triggered arrhythmias 2+ Net effect: increases amplitudes and accelerates relaxation of Ca transients and pressure plus increases arrhythmias Ryanodine receptors: RyR2 2+ - increases P oO RyR2 and Ca release from cluster/couplons by reducing calstabin2 binding 2+ 2+ - Increases P aOd Ca release from cluster/couplons by increasing SR Ca levels - increases spontaneous Ca 2+ and arrhythmias 2+ Net effect: increases amplitudes relaxation of Ca transients and pressure plus increases arrhythmias 4
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