Cell Surface Receptors and Their Signal Transduction
1. The seven transmembrane G protein–coupled receptors
They are localized in the plasma membranes of cells in such a manner as to have seven transmembrane domains, with multiple extracellular and intracellular domains. This group of receptors is the most heterogeneous of the cell surface receptors and communicates with intracellular components by activating specific guanine nucleotide- binding (G) protein intermediates.
a. Gs-coupled receptors (e.g., b-adrenergic, vasopressin V2, glucagon, dopamine D1)
These receptors are functionally coupled to adenylyl cyclase, which catalyzes the conversion of adenosine triphosphate (ATP) to cyclic adenosine monophosphate (cAMP), an intracellular second messenger (Figure 1). cAMP is responsible for the downstream activation of protein kinase A (PKA), a multifunctional enzyme that alters the function of multiple substrates to ultimately produce effects such as increases in heart rate, release of glucose from the liver, decrease water loss in the kidneys, and increase neurotransmitter release.
Figure 1: The cAMP-PKA signaling system is responsible for diverse biological effects such as increased heart rate/contractility, vasodilation, and neurotransmitter release. Epi, epinephrine; GS, guanine nucleotide-binding protein; ATP, adenosine triphosphate; cAMP, cyclic adenosine monophosphate; PKA, protein kinase A.
b. Gq-coupled receptors (e.g., a1-adrenergic, muscarinic M1, angiotensin AT1)
Binding of endogenous ligands such as norepinephrine or acetylcholine leads to conformational change in the relevant receptor and activation of the associated Gq protein, which in turn activates a membrane-bound phospholipase C. This enzyme catalyzes the hydrolysis of membranous phosphatidylinositol bisphosphate (PIP2) resulting in the production of inositol trisphosphate (IP3) and diacylglycerol (DAG). The hydrophilic IP3 releases stored calcium from the sarcoplasmic reticulum, whereas DAG activates protein kinase C (Figure 2). These processes are eventually responsible for biological processes such as smooth muscle contraction, aldosterone release, salivary secretion, etc.
Figure 2: The phosphoinositide signaling system is responsible for physiological responses such as salivary secretion, smooth muscle contraction, and hormone release. ACh, acetylcholine; Gq, guanine nucleotide-binding protein; PLC, phospholipase C; IP3, inositol trisphosphate; DAG, diacylglycerol; PKC, protein kinase C; PIP2, phosphatidylinositol bisphosphate.
c. Gi/o-coupled receptors (e.g., muscarinic M2, a2-adrenergic, opioid)
The best characterized results of activating receptors coupled to Gi/o proteins is the decrease in intracellular cAMP and opening of K1-channels leading to hyperpolarization. The overall response of these types of events is inhibitory and leads to responses such as decreasing heart rate and inhibition of neurotransmitter release.
2. Ion channels
They are found on the membranes of excitable cells (cardiac muscle, nerve cells, etc.) are important regulators of cellular function and serve as targets for pharmacological intervention.
a. Ligand-gated channels (e.g., nicotinic, GABAA, glutamate)
The binding of endogenous ligands (acetylcholine, GABA, etc.) on the extracellular domains allows the opening of ionselective pores on the protein that allow for the movement of ions such as sodium, chloride, or calcium. Depending on the ion being conducted, the eventual physiological response may be skeletal muscle contraction, nerve depolarization, or hyperpolarization.
b. Voltage-gated channels (e.g., calcium, sodium, potassium channels)
Depolarizing currents lead to opening of these channel proteins, allowing the selective movement of specific ions into (calcium, sodium) or out (potassium) of the cell. These ion fluxes lead to cell depolarization (calcium, sodium) or repolarization (potassium) in a coordinated fashion to regulated muscle contraction and nerve action potential.
3. Growth factor receptors (e.g., epidermal growth factor [EGF] receptor, insulin receptor, fibroblast growth factor receptor, interleukin-2 receptors)
Generally, these receptors are composed of a single transmembrane domain containing a cytoplasmic tyrosine kinase. Thus, binding of EGF to its receptor results in receptor dimerization, activation of the tyrosine kinase motif, followed by cross phosphorylation of their cytoplasmic tail regions. This tyrosine phosphorylation on specific sequences serves to produce src-homology binding domains for the docking of additional proteins that transduce the signal to the interior of the cell.
Consequently, EGF receptor activation leads to recruitment of Grb/Sos to the receptor with subsequent activation of the extracellular signal-regulated kinase (ERK) pathway to promote cell growth/replication (Figure 3). Similarly, insulin binding and receptor activation promotes insulin receptor substrate 1/2 (IRS-1/IRS-2) recruitment that increases plasma membrane glucose transporter expression and enhanced glucose uptake.
Figure 3: The ERK-MAPK signaling pathway mediates the biological processes of growth and differentiation. EGF, epidermal growth factor; MEK, ERK-kinase; ERK, extracellular signal-regulated kinase.
4. Membrane transporters, pumps, and miscellaneous receptors (e.g., Na1/K1-ATPase, MDR- 1 protein, natriuretic factor receptors)
The natriuretic peptide family of proteins activates membrane- bound, single-transmembrane domain receptors that contain cytoplasmic guanylyl cyclase activity. Membrane-bound pumps such as the Na/K ATPase and the MDR-1/P-glycoprotein are also targets for various therapeutic interventions even though they do not have well- characterized endogenous ligands.
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