Transcript File
Subtypes of Alpha Adrenergic Receptors Alpha1A – contraction of smooth muscle – high density in prostate gland; also found on arteries and veins Alpha1B – most abundant type in heart (function??), may be involved with alpha 1A in cardiac growth and structure, may be more abundant on blood vessels as we get older; Alpha1C was discovered and named but was later found to be the same as alpha1B Alpha1D – found on coronary blood vessels and aorta – importance? Alpha2A – inhibitory autoreceptor found on presynaptic nerve endings of sympathetic and also parasympathetic nerves; found in CNS and stimulation associated with hypotension and antinociceptive responses Alpha2B – on peripheral blood vessels, low density, can produce constriction Alpha2C – predominately inhibitory – found in adrenal medulla and on nerve endings to inhibit release of E and dopamine, respectively Intrinsic Mechanisms Produced By Receptor Activation Muscarinic 2 receptors: Gi/Go – inhibits adenylyl cyclase, inactivates calcium channels, increases potassium efflux – hyperpolarization INHIBITORY Muscarinic 3 receptors: Gq/11 protein – increase phopholipase C activity, increase formation of IP3 and DAG, increase intracellular calcium CONTRACTION (in most cells – exception – vascular smooth muscle cells) Alpha one receptors: Gq/11 protein – same as muscarinic 3 receptor mechanism - CONTRACTION Alpha 2 receptors: Gi/Go protein – same as muscarinic 2 receptor mechanism – INHIBITORY Beta one receptors: Gs proteins – increase activity of adenylyl cyclase, increase intracellular calcium – EXCITATORY Beta 2 receptors: Gs proteins – increase activity of adenylyl cyclase activity in most smooth muscle cells, decrease intracellular calcium INHIBITORY CLASSIFICATION OF RECEPTORS Adrenergic Receptors (all are GPCRs) Dr. Raymond Alquist - 1948 Alpha one receptors – vascular and nonvascular smooth muscle, Gq protein – contraction Alpha two receptors – presynaptic nerve terminals, pancreatic beta cells, vascular smooth muscle, Gi/Go protein – inhibitory most of the time (exception on vascular smooth muscle) Beta one receptors – heart, J-G cells within kidneys, Gs proteins – excitatory Beta two receptors – smooth muscle (vascular, bronchial, GI and UT), Gs protein – inhibitory Beta three receptors – adipose tissue, Gs protein – lipolysis Receptors at Neuroeffector Junction Involuntary Contraction Of Cardiac Cell Ca++ Voltage-gated Channel Depolarization of Cell Sarcoplasmic Ca++ Reticulum Increased Contraction Cardiac Cell ACh M2 receptor inhibits Gi or o protein K+ Hyperpolarization Inactive Protein Kinase A Inactivates channel Ca++ adenyl cyclase ATP cAMP AC – open calcium channel PKA – opens calcium channel and releases Ca++ from SR Active Protein Kinase A Sarcoplasmic Reticulum Decreased Contraction or Relaxation Cardiac Cell STIMULI Voltage-gated channel Calmodulin On Myosin Ca++ Ca++ Calmodulin Complex MLCK MLCK* ATP Myosin Light Chain Myosin Phosphatase RELAXATION Myosin Light Chain – PO4 Myosin Actin CONTRACTION Smooth Muscle Cell ACh PIP2 PLC M3 Receptor DAG Ca++ IP3 Ca++ Protein Kinase C Calmodulin ATP Calmodulin Complex MLCK Myosin Light Chain ADP PO4 MLCK* Myosin Light Chain – PO4 Actin CONTRACTION PIP2 = phosphatidyl inositol biphosphate IP3 = Inositol triphosphate DAG = Diaacylglycerol Smooth Muscle Cell Anatomy of a Blood Vessel Acetylcholine Muscarinic 3 Receptor PIP2 PLC IP3 L-Arginine Ca++ Calmodulin Ca++-Calmodulin Complex Nitric Oxide Endothelial Cell Lining Blood Vessel Lumen L-Citrulline Muscarinic 3 Receptor R E L A X A T I O N Sarcoplasmic Reticulum Ca++ Ca++ Cyclic GMP GTP Calmodulin Calmodulin Complex MLCK* MLCK Myosin Light Chain Myosin Light Chain – PO4 Actin Myosin Phosphatase PLC CONTRACTION Vascular Smooth Muscle Cell NE Receptors at Neuroeffector Junction G Protein-Coupled Receptor Second Messenger Receptor Ca++ Effector Protein (Adenyl Cyclase) β GTP cAMP ATP α GDP Beta receptor γ RESPONSE GDP PDE 5’AMP NE PIP2 PLC Alpha1 DAG Ca++ IP3 Ca++ Protein Kinase C Calmodulin ATP Calmodulin Complex MLCK Myosin Light Chain ADP PO4 MLCK* Myosin Light Chain – PO4 Actin CONTRACTION Smooth Muscle Cell Alpha 2 Presynaptic Alpha 2 Receptor Agonist Gi or o protein K+ Hyperpolarization inhibits Ca++ Inactivates channel adenyl cyclase ATP cAMP Decrease Release of Neurotransmitter Presynaptic Nerve Terminal or CNS NE Beta-1 Receptor Gs protein ATP Inactive Protein Kinase A Ca++ Ca++ adenyl cyclase cAMP Active Protein Kinase A Enhance actin and myosin interaction Sarcoplasmic Ca++ Reticulum Increased Ca++ Binding to troponin Increased Contraction Cardiac Cell Epi., Albuterol Terbutaline Beta Two Receptor Adenyl Cyclase cAMP ATP Ca++ Ca++ Calmodulin Calmodulin Complex MLCK MLCK* *(inactive) Myosin Light Chain K+ Myosin Light Chain – PO4 CONTRACTION RELAXATION Actin Hyperpolarizatiion Smooth Muscle Cell Responses of Effector Organs to Autonomic Nerve Impulses Sympathetic and Parasympathetic TONE Continually active – SNS: Blood Vessels - maintain peripheral resistance PNS: Heart Loss of sympathetic tone increase in intrinsic tone of smooth muscle Denervation Supersensitivity α1 α1 α1 α1 α1 α1 Sympathetic or Parasympathetic stimulation of receptors can result in Excitatory Effects in some organs but Inhibitory Effects in others! Frequently, if sympathetic stimulation causes excitation in an organ, parasympathetic stimulation to that same organ will result in inhibition.