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 anti- nociceptive 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

Adrenergic Receptors (all are GPCRs) 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

Depolarization of Cell Receptors at Neuroeffector Junction Involuntary Contraction Of Cardiac Cell Ca++ Ca++ Voltage-gated Channel Depolarization of Cell Sarcoplasmic Reticulum Ca++ Cardiac Cell Increased Contraction

AC – open calcium channel PKA – opens calcium channel M2 receptor Ca++ ACh Inactivates channel inhibits adenyl cyclase Gi or o protein K+ AC – open calcium channel PKA – opens calcium channel and releases Ca++ from SR ATP cAMP Hyperpolarization Inactive Protein Kinase A Active Protein Kinase A Sarcoplasmic Reticulum Cardiac Cell Decreased Contraction or Relaxation

Ca++ Ca++ STIMULI Voltage-gated channel Sarcoplasmic Reticulum MLCK Calmodulin On Myosin Ca++ Sarcoplasmic Reticulum Ca++ Calmodulin Complex MLCK MLCK* ATP Myosin Light Chain Myosin Light Chain – PO4 Myosin Phosphatase Myosin Actin RELAXATION CONTRACTION Smooth Muscle Cell

Ca++ ACh PLC Ca++ IP3 Smooth Muscle Cell PIP2 M3 Receptor DAG Gq Protein Ca++ IP3 Ca++ Sarcoplasmic Reticulum Protein Kinase C Calmodulin ATP ADP Calmodulin Complex PO4 MLCK MLCK* Myosin Light Chain Myosin Light Chain – PO4 Actin CONTRACTION Smooth Muscle Cell PIP2 = phosphatidyl inositol biphosphate IP3 = Inositol triphosphate DAG = Diaacylglycerol

Anatomy of a Blood Vessel

Ca++ eNOS Nitric Oxide Acetylcholine Muscarinic 3 Receptor PLC IP3 Gq Protein PLC PIP2 IP3 eNOS Sarcoplasmic Reticulum L-Arginine Ca++ Calmodulin Ca++-Calmodulin Complex Nitric Oxide L-Citrulline Endothelial Cell Lining Blood Vessel Lumen

R E L A X T I O N Nitric Oxide Ca++ Ca++ Cyclic GMP GTP Ca++ PLC Muscarinic 3 Receptor R E L A X T I O N Sarcoplasmic Reticulum Ca++ Ca++ Myosin Light Chain Calmodulin Calmodulin Complex MLCK MLCK* CONTRACTION Actin Cyclic GMP Guanyl Cyclase GTP inhibits Ca++ Myosin Light Chain Myosin Light Chain – PO4 Myosin Phosphatase PLC Vascular Smooth Muscle Cell

α PDE Receptors at Neuroeffector Junction NE Ca++ β γ cAMP ATP GTP GDP G Protein-Coupled Receptor Second Messenger Receptor Ca++ Effector Protein (Adenyl Cyclase) β γ α cAMP ATP GTP GDP GDP 5’AMP Beta receptor PDE RESPONSE

Ca++ NE Smooth Muscle Cell PLC Ca++ IP3 PIP2 Alpha1 DAG Sarcoplasmic Gq Protein Ca++ IP3 Ca++ Sarcoplasmic Reticulum Protein Kinase C Calmodulin ATP ADP Calmodulin Complex PO4 MLCK MLCK* Myosin Light Chain Myosin Light Chain – PO4 Actin CONTRACTION Smooth Muscle Cell

Decrease Release of Neurotransmitter Alpha 2 Presynaptic Ca++ Alpha 2 Receptor Agonist Inactivates channel inhibits adenyl cyclase Gi or o protein K+ ATP cAMP Hyperpolarization Decrease Release of Neurotransmitter Presynaptic Nerve Terminal or CNS

Cardiac Cell Ca++ Ca++ NE Ca++ ATP cAMP Ca++ Increased Contraction Beta-1 Receptor Ca++ Ca++ NE Ca++ adenyl cyclase Gs protein ATP cAMP phosphorylation Inactive Protein Kinase A Active Protein Kinase A Enhance actin and myosin interaction Sarcoplasmic Reticulum Ca++ Increased Ca++ Binding to troponin Cardiac Cell Increased Contraction

cAMP Ca++ Smooth Muscle Cell ATP Ca++ K+ RELAXATION Epi., Albuterol Terbutaline Adenyl Cyclase Gs Protein Beta Two Receptor cAMP ATP Ca++ act. PKa Sarcoplasmic Reticulum Ca++ phosphorylation abnormal Calmodulin Calmodulin Complex K+ MLCK MLCK* *(inactive) Myosin Light Chain Myosin Light Chain – PO4 Actin CONTRACTION Hyperpolarizatiion RELAXATION 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 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.