The water-soluble hormones, peptides and catecholamines, bind to plasma membrane receptors on the outside surface of the cell. There are several categories of plasma membrane receptors including: Receptors that activate G proteins and receptors with protein kinase activity. We will examine the most common G protein mechanisms and the protein kinases called tyrosine kinases that phosphorlate tyrosine. We will look each kind of receptor beginning with the receptors that activate G proteins. In the inactivated state, guanosine diphosphate, GDP, is bound to the G protein. When a hormone binds to the receptor, the receptor changes its shape and activates the G protein. It releases GDP and binds guanosine triphosphate, GTP, a high energy molecule. Part of the activated G protein travels along the membrane and activates an enzyme called adenylate cyclase. Adenylate cyclase catalyzes the conversion of adenosine triphosphate, ATP, to cyclic adenosine monophosphate. Cyclic AMP is a second messenger. The hormone is the first messenger. Cyclic AMP activates the intracellular enzyme protein kinase A, which can phosphorylate many other proteins, activating some and inhibiting others. This mechanism can induce many different effects within a single cell and different actions in different cell types. This second messenger system can also phosphorylate ion channels and alter their activity. The response of the cell ends when cyclic AMP is degraded to AMP in a reaction catalyzed by the enzyme phosphodiesterase. While active, G proteins keep stoking the pathway to phosphorlation of cellular proteins, so that huge numbers of them are produced. This phenomenon called amplification greatly increases the effect that a single molecule of a hormone can have on a cell. G proteins, like the one we just described, that stimulate production of cyclic AMP are known as stimulatory G proteins. Inhibitory G proteins inhibit production of cyclic AMP and the subsequent response of the cell. Another type of G protein activates an intracellular messenger system that uses diacylglycerol and inositol trisphosphate as second messengers. When a hormone binds to the receptor, the receptor changes shape and activates the G protein. It releases GDP and binds GTP, a high-energy molecule. Part of the activated G protein travels along the membrane and activates an enzyme called phospholipase C. Phospholipase C causes a membrane phospholipid called phosphatidylinositol (PIP2) bisphosphate to cleave into diacylglycerol and inositol trisphosphate (IP3). Each functions as a second messenger. Diacylglycerol remains in the membrane where it actives protein kinase C and inositol trisphosphate enters the cytosol. The activated protein kinase C phosphorylates other proteins causing responses of the cell. Inositol trisphosphate prompts the endoplasmic reticulum to release calcium irons. Calcium ions also behave like second messengers. They can act directly on proteins or bind to the protein calmodulin that can act on proteins to cause the response of the cell. Another type of plasma membrane receptor utilizes protein kinase activity for its effect. An example of this are hormones that bind to tyrosine kinase receptors. Let’s place each hormone in a binding site on the receptor to observe its activity. When a hormone binds to a tyrosine kinase receptor, the receptor joins with the neighboring receptor and changes shape. Each receptor phosphorylates tyrosine groups in its neighbor. The process is called autophosphorylation because the receptors are of the same type. The phosphorylated tyrosine groups provide docking sites where relay proteins bind. They initiate a series of protein phosphosylations that lead to the response of the cell. Receptors with tyrosine kinase activity often bind hormones like insulin and other growth factors that affect cell growth and differentiation. Now we will study mechanisms used by epinephrine and insulin to induce cellular responses. Nearly all body cells express receptors for epinephrine and norepinephrine, called adrenergic receptors. There are two families of adrenergic receptors,alpha and beta, with each member of the family designated by a number. All adrenergic receptors bind both epinephrine and norepinephrine, although with different affinities. All adrenergic receptors activate G proteins. Beta receptors are coupled to adenylate cyclase by stimulatory G proteins that increase cyclic AMP activity. Alpha 2 receptors are coupled to adenylate cyclase by inhibitory G proteins that decrease cyclic AMP activity often blocking the increase is induced by other agents. Alpha 1 receptors act via the IP3, DAG, and calcium second messenger system. Some cellular responses to these catecholamines are listed beneath the appropriate receptors. Blood flow is redirected to working muscles where increased cardiac output delivers increased fuel and oxygen. Fuel molecules are released from stores and made available for use by working muscles. The airways dilate to maximize gas exchange. Note that all of these effects support the fight or flight response. Insulin acts primarily on liver, adipose tissue, skeletal muscle, and cardiac muscle by binding to tyrosine kinase receptors. Each tissue responds differently and each has multiple responses. Some of the cellular responses to insulin are listed beneath the receptors: Glucose uptake increases in all three major tissue types. Insulin stimulates glycogen synthesis in muscle and liver cells and triglyceride synthesis in adipose and liver cells. Amino acid uptake and protein synthesis are stimulated in muscle. Note that these effects support the overall goal of promoting storage of fuel molecules.