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The dystrophin glycoprotein complex (DGC) and associated proteins at the muscle cell plasma membrane. The dystrophin glycoprotein complex links the extracellular matrix to cytoskeletal elements. β-dystroglycan is the only component of the DGC that directly interacts with dystrophin. The WW domain within dystrophin and the WW-like domain within caveolin-3 both bind to the PPXY motif at the C-terminus of β-dystroglycan. Up-regulation of caveolin-3 (as seen in Duchenne muscular dystrophy patients, in mdx mice, and in caveolin-3 over-expressing transgenic mice) can displace dystrophin from the plasma membrane, inducing destabilization and, eventually, degradation of the protein. Arrows indicate diseases caused by the absence (-) or up-regulation (+) of the indicated protein. DMD, Duchenne muscular dystrophy; BMD, Becker muscular dystrophy; CMD, congenital muscular dystrophy; LGMD-1C, -2C, -2D, -2E, -2F, Limb-girdle muscular dystrophy type 1C, -2C, -2D, -2E, -2F; nNOS, neuronal form of nitric oxide synthase; CSD, caveolin scaffolding domain; CBD, caveolin binding domain. Modified from Ref #.56

A diagram showing some of the synaptic connections that have been identified in the rodent superficial dorsal horn. Three projection neurons are shown in grey. One of these is a lamina I giant cell, while the other two are NK1r-expressing projection neurons (PN) with their cell bodies in laminae I and III. Note that the lamina III cell has prominent dorsal dendrites that enter the superficial laminae. Both types of NK1r-expressing PN are densely innervated by substance P-containing primary afferents, while the lamina III cells also receive an input from myelinated low threshold mechanoreceptive (LTM) afferents. The giant cells receive dense synaptic input from GABAergic inhibitory interneurons, many of which contain neuronal nitric oxide synthase (GABA/nNOS), and from glutamatergic excitatory interneurons of unknown origin (GLU IN). The lamina III NK1r PN is densely innervated by NPY-containing GABAergic interneurons and dynorphin (DYN)-containing glutamatergic interneurons. Glutamatergic vertical cells, which receive monosynaptic input from small myelinated (Aδ) afferents are presynaptic to the lamina I NK1r PNs. Parvalbum-containing GABAergic islet cells (GABA/PV) receive direct input from myelinated LTM afferents and their axons form axoaxonic synapses with the same type of afferent. For further information, see text.

Vasomotor control mechanisms operant in skeletal muscle in the endothelium and vascular smooth muscle cells in the walls of arteries and arterioles (upper panel). Lower panel illustrates some of the more prominent receptors, ion channels, and signaling pathways that operate to modulate vascular smooth muscle tone in skeletal muscle as these emphasize the complex nature of the neurohumoral and metabolic regulatory systems involved in the control of vascular resistance in skeletal muscle at rest and during exercise. The illustration is not meant to be all-inclusive. Pericytes are not depicted, but are discussed in the text, as these contractile cells may also participate in vasomotor control. Modified from reference [365]. In both panels, the internal elastic lamina (basement membrane) between the endothelium and vascular smooth muscle is omitted for clarity.
Abbreviations: K_Ca, calcium-activated K⁺ channel; K_ATP, ATP-sensitive K⁺ channel; K_v, voltage-gated K⁺ channel; K_IR, inward rectifying K⁺ channel; Trp, transient receptor potential channels; O₂, oxygen; ATP, adenosine triphosphate; NO, nitric oxide; TXA₂, thromboxane A₂ and receptor; 5HT, 5-hydroxytryptamine and receptor; PMNs, polymorphonuclear leukocytes; O₂^-, superoxide anion radical; H₂O₂, hydrogen peroxide; TNF, tumor necrosis factor α; LTC₄, leukotriene C₄; MMP, matrix metalloproteinases; P2, purinergic type 2 receptor; M, muscarinic receptor; MEJ, myoendothelial junction; H₁ and H₂, histamine receptors; B₂, bradykinin receptor; TNFR, tumor necrosis alpha receptor; LTR, leukotriene receptor; ECE, endothelin-converting enzyme; bET-1, big endothelin-1; ET-1, endothelin-1; eNOS, endothelial nitric oxide synthase; L-Arg, L-arginine; COX-1, cyclooxygenase 1; CYP450, cytochrome P450 epoxygenase; ACE, angiotensin-converting enzyme; AI, angiotensin I; AII; angiotensin II; AT₁, angiotensin type 1 receptor; AT₂, angiotensin type 2 receptor; ET_A, endothelin type A receptor; ET_B, endothelin type B receptor; PG, prostaglandins; AA, arachidonic acid; EDHF, endothelium-derived hyperpolarizing factor; VGCC, voltage-gated calcium channels; IP, prostacyclin receptor; EETs, epoxyeicosatrienoic acids; HETEs, hydroxyeicosatetraenoic acids; α₁, α₁-adrenergic receptor; α₂, α₂-adrenergic receptor; β₂, β₂-adrenergic receptor; ACh, acetylcholine; NE, norepinephrine; NPY, neuropeptide Y; P1, purinergic type 1 receptor; Y₁, neuropeptide Y receptor; IL, interleukin-6 receptor; CGRP, calcitonin gene-related peptide; CLR, calcitonin-like receptor.

L-arginine–NO-synthase–soluble guanylyl cyclase pathway and potential sites of therapeutic intervention. The circled numbers (from 1 to 14) indicate potential sites of therapeutic intervention. (1) L-arginine supplementation. (2) Inhibition of protein arginine N-methyltransferase type I (PRMT-I) to prevent the formation of asymmetric dimethyl-L-arginine (ADMA). (3) Increasing the expression and/or the activity of dimethylarginine dimethylaminohydrolase-2 (DDAH-2) to facilitate ADMA catabolism. (4) Inhibition of arginase-2 to prevent L-arginine metabolism. (5) Increasing the expression and/or activity of endothelial nitric oxide synthase (eNOS). (6) Designing drugs that stimulate endothelium-derived nitric oxide release. (7) Enhancing the expression and/or activity of guanosine triphosphate cyclohydrolase (GTPCH), the rate limiting enzyme for tetrahydrobiopterin synthesis (BH4), or direct supplementation with BH4, or with its precursor sepiapterin. (8) Enhancing the expression and/or activity of dihydrofolate reductase (DHFR), involved in BH4 regeneration. (9) Scavengers of reactive oxygen species (ROS), antioxidants. (10) Inhibition of the activity and/or expression of enzymes that generate ROS such as NAD(P)H oxidases (NOX), cyclooxygenases (COX), lipooxygenases (LOX) or cytochrome P450 monooxygenases (P450). (11) Enhancing the expression and/or activity of enzymes that metabolized ROS such as superoxide dismutase (SOD) or catalase (or alternatively synthesis of mimetics). (12) Stimulators of soluble guanylyl cyclase (sGC). (13) Activators of sGC. (14) Inhibitors of phosphodiesterase-5 (PDE-5). EC: endothelial cell; VSMC: vascular smooth muscle cell; CAT-1: cationic amino acid transporters; FMN: flavin mononucleotide; FAD: flavin adenine dinucleotide; BH2: dihydrobiopterin; O₂.^-: superoxide anion; ONOO^-: peroxynitrite; cGMP: cyclic guanosine monophosphate; PKG: protein kinase G, CaV: voltage-activated calcium channel.